More than 4 million Americans are currently being treated for cancer. Each year, 1.3 million Americans are newly diagnosed with cancer. For the past four decades, both the incidence and age-adjusted death rate from cancer in America have been climbing steadily.
Cancer is an abnormal growth, caused by underlying disease involving the whole body. It is not just limited to a lump or bump. The successful treatment of cancer is best accomplished by the precise administration of multiple therapies. Neither conventional nor alternative medicine recognizes the importance of multimodality treatment, and the end result is that too many cancer patients needlessly die.
Although the mainstream therapies of chemotherapy, radiation, and surgery often do reduce tumor burden, these therapies do not change the underlying causes of the disease. Given the blatant failures of conventional cancer therapies, it is imperative that we examine optional and complementary therapies to assist the swelling ranks of American cancer patients. These therapies need to be considered earlier, rather than as a last resort by cancer patients.
The purpose of this protocol is to help cancer patients bridge critical gaps in their treatment programs so they can increase the odds of long-term disease remission. The information provided is based solely on peer-reviewed studies published in respected medical journals throughout the world. It is important for the reader to know that this protocol is based on the results of published research, as there are many fraudulent "cancer cures" that are not substantiated in the medical literature.
We call these "adjuvant" treatment recommendations because the primary therapy will inevitably be administered by the attending physician. The problem is that even the best oncologist may not be able to keep up with the latest findings because of the sheer volume of new treatment data. Our mission, therefore, is to provide insightful cancer-treatment information that is too often overlooked by practicing oncologists.
It is of critical importance in any cancer treatment program to measure success or failure. This can be accomplished in most cancers by evaluating tumor markers in the blood and/or by looking at the actual tumor(s) via medical imagery. When using any kind of cancer therapy, it is crucial that blood tumor marker tests be performed every 30 to 45 days. If the tumor markers reveal regression of the cancer, then existing therapy may be continued. If tumor markers indicate disease progression, then a different treatment approach should be implemented immediately. At the end of this protocol, we provide a listing of blood tumor marker tests as they relate to specific types of cancer.
Many types of cancer cells use an enzyme called cyclooxygenase-2 (COX-2) to propagate. This includes cancers of the colon, pancreas, breast, prostate, bladder, lung, head and neck, to name a few. The good news is that COX-2 is also involved in the rheumatoid arthritis process, so there are drugs that are already approved to treat arthritis that may also be prescribed for cancer patients.
Drugs that inhibit the cyclooxygenase enzyme are known as COX-2 inhibitors. The two newest COX-2 inhibitors are Celebrex and Vioxx, but we suggest that cancer patients consider older drugs that have a more predictable safety history. One drug that oncologists may consider prescribing is Lodine XL, a drug used to treat arthritis that also interferes with COX-2 activity. A safer COX-2 inhibiting drug called nimesulide is sold in Europe but is not yet approved by the FDA.
Cancer cells often produce large amounts of COX-2 and use it as a biological fuel to cause rapid proliferation of cell division. An article in the journal Cancer Research (1999 March 1; 59 :987-90) shows that COX-2 levels in pancreatic cancer cells are 60 times greater than in adjacent normal tissue. A handful of physicians knowledgeable about COX-2 and cancer are prescribing COX-2 inhibitors to their patients. It was back in 1997 that the Life Extension Foundation recommended the European drug nimesulide to cancer patients. The FDA has aggressively blocked the personal-use importation of this potential life-saving medication to cancer patients.
Scientists are now actively investigating COX-2 inhibitors as drugs that would be effective in both the prevention and treatment of many cancers. When COX-2 drugs are given to patients with colon polyps (precancerous lesions), the lesions completely disappear. When a group of rats were given a potent carcinogen, there was a 90% reduction in those who developed cancer if they were on COX-2 inhibition therapy. In the few rats that did develop the tumors while taking COX-2 inhibition therapy, the tumors were 80% smaller and less numerous than in the group not on COX-2 inhibition (Wall Street Journal, Sept. 7, 1999).
We predict that COX-2 inhibiting drugs will eventually be approved to treat cancer, but in the meantime, cancer patients should ask their doctors to consider prescribing a COX-2 inhibiting drug as an adjuvant therapy.
Lodine XL is an arthritis drug approved by the FDA that interferes with COX-2 metabolic processes. The maximum dosage for Lodine is 1000 mg daily. Everyone now appears to be using Lodine XL extended-release tablets for convenient once-a-day dosing. The Lodine XL 500-mg tablet enables physicians to prescribe the maximum dosage of Lodine XL-1000 mg per day-as two tablets in a single daily dose. As with any nonsteroidal anti-inflammatory drug (NSAID), extreme caution and physician supervision are a must.
The most common complaints associated with Lodine XL use relate to the gastrointestinal tract. Serious GI toxicity such as perforation, ulceration, and bleeding can occur in patients treated long term with NSAID therapy. Serious renal and hepatic reactions have been reported only rarely. Lodine XL should not be given to patients who have previously shown hypersensitivity to it or in whom aspirin or other NSAIDs induce asthma, rhinitis, urticaria, or other allergic reactions. Fatal asthmatic reactions have been reported in such patients receiving NSAIDs.
Nimesulide is a safer COX-2 inhibitor, but is not approved by the FDA. It is available from Mexican pharmacies or can be ordered by mail from European pharmacies. The suggested dose for nimesulide is two 100-mg tablets a day. It is important that your physician know you are taking nimesulide as an adjuvant cancer therapy. Please refer to the "molecular oncology" section of this protocol for a detailed description of the connection between COX-2 and cancer.
The regulation of cancer cell growth is often governed by a family of proteins known as RAS oncogenes. The RAS family is responsible for modulating the regulatory signals that govern the cancer cell cycle and proliferation. Mutations in genes encoding RAS proteins have been intimately associated with unregulated cell proliferation (i.e., cancer).
There is a class of cholesterol-lowering drugs known as the "statins" that have been shown to inhibit the activity of RAS oncogenes. Some of these cholesterol-lowering "statin" drugs are lovastatin, simvastatin, and pravastatin.
The highest incidences of RAS mutations are found in cancers of the pancreas (90%), the colon (50%) and the lung; in thyroid tumors (50%), in liver tumors (30%), and in myeloid leukemia (30%). If you have one of these cancers, you should consider requesting an immunohistochemistry for the mutated RAS oncogene or a biopsied specimen in order to ascertain whether the combination of chemotherapy and a statin drug may be effective. (Information about obtaining RAS testing appears later in this protocol.)
As far as dosing is concerned, if the drug lovastatin (Mevacor) were chosen, a cancer patient with a mutated RAS oncogene should take as high as 80 mg a day for several months. Another approach is to take 80 mg a day of lovastatin for 3 weeks, take 2 weeks off, and then resume. It may be especially important to use a statin drug during chemotherapy. Statin drugs given with cytotoxic chemotherapy could provide the necessary one-two punch to kill a sufficient number of tumor cells for the patient to enter a period of long-term remission. Careful monitoring of liver enzymes is needed to guard against liver toxicity of the statin drugs. There are other potential side effects to watch out for, but in many cancers, statin drugs appear to be a powerful inhibitor of cancer cell proliferation. The "molecular oncology" section of this protocol provides more details about the use of statin drugs as an adjuvant cancer therapy.
A novel approach would be to combine a "statin" drug such as lovastatin with a COX-2 inhibitor.
A study published in the journal Gastroenterology (1999, Vol. 116, No. 4, Suppl. A369) showed that lovastatin augmented by up to fivefold the cancer cell killing effect of a drug with COX-2 inhibiting properties (Sulindac). In this study, three different colon cancer cell lines were killed (made to undergo programmed cell death) by depriving them of COX-2. When lovastatin was added to the COX-2 inhibitor, the kill rate increased by up to fivefold.
Thus, those with certain cancers might benefit if their oncologists prescribed for several months 80 mg a day of Mevacor (lovastatin) and 1000 mg a day of Lodine XL.
Physician involvement is crucial to help protect against potential side effects of these drugs. Those who are concerned about potential toxicity should take into account the fact that the types of cancers these drugs might be effective against have extremely high mortality rates.
Nutrition therapy helps to change the conditions in the body that favor tumor growth and return the cancer patient to a healthier status. More wellness in the body means less illness. Fungus grows on the bark of a tree due to the underlying conditions of heat, moisture, and darkness. One could "cut, burn, and poison" this fungus, but as long as the prevailing conditions of heat, moisture, and darkness were present, the fungal growth would return until the host was consumed. Similarly, a patient develops cancer due to a collection of conditions that compromise the host.
Nutrition is a low-cost, nontoxic, and scientifically validated adjuvant modality in the treatment of cancer. Adjuvant (helpful) nutrition and traditional oncology are synergistic, not antagonistic. Some reasons and rationale for using an aggressive nutrition program in comprehensive cancer treatment include
A complete nutritional support plan of action will be provided later in this protocol.
Angiogenesis (new blood vessel growth) is a key step in tumor growth, invasion, and metastasis. A substance that cuts the supply of blood to cancer cells can stop the primary tumor and its spread throughout the body. A new anti-angiogenesis cancer drug will enter human clinical trials in the United States at the end of 1999. The scientific literature shows that this drug induces a consistent and significant reduction in tumor growth in laboratory animals. In many cases the primary and metastatic cancer lesions are put into a dormant state and no longer propagate.
To date, a number of anti-angiogenesis agents have been identified. In animal models, treatment with angiogenesis inhibitors has proven anti-tumor effects. Early clinical experience with angiogenesis inhibitors indicates that optimal anti-angiogenesis therapy will likely be based on their long-term administration to cancer patients in adjunct to other therapies.
The published evidence indicates that the new angiogenesis-inhibitors offer great promise to cancer patients. The therapy is nontoxic and has shown efficacy against every type of cancer it has been tested against. One study showed that it suppressed metastatic tumor growth rates by 90%. Another study showed primary tumors regressing to become "dormant microscopic lesions."
Before raising any premature hope, we want to state that this new anticancer therapy consists of two drugs, endostatin and angiostatin. The FDA, however, is only permitting one of these two drugs (endostatin) to be used in the initial clinical trials. In other words, the FDA is not allowing terminally ill humans to use the two drugs that worked so remarkably well together in the animal studies. There is still reason to believe, however, that just one half of this drug combination (the endostatin) could save the lives of human cancer victims who have been sentenced to death by the medical establishment.
Those suffering from a nontreatable form of cancer should consider entering those clinical trials where endostatin, a potent angiogenesis-inhibiting drug, will be tested in humans. It is hoped that the other angiogenesis-inhibiting drug, angiostatin, will soon be added to endostatin in order to replicate the successful two-drug combo that so effectively treated cancer in the laboratory studies.
Primary and metastatic tumors require ongoing angiogenesis (new blood vessel formation) to support their growth. This is an undisputed fact based on today's understanding of oncological processes. Weak angiogenesis-inhibiting agents such as shark cartilage have not shown adequate efficacy. Angiostatin and endostatin are naturally produced proteins that shut off new blood vessel formation to tumors.
Angiostatin and/or endostatin have produced dramatic remissions in animal studies. Human cancer patients can access endostatin in FDA- sanctioned human clinical trials. The drug endostatin is derived from a protein found in the human body. In animal trials, the protein drug wiped out several forms of cancer by choking off the blood supply to tumors.
Although many cancer patients develop a resistance to conventional drugs, they aren't likely to do so with endostatin. What's more, the new natural treatment appears to stop cancer from spreading to other parts of the body.
So far, endostatin has worked only in mice. Now the National Cancer Institute in Frederick, MD, wants to find out whether the drug can starve human tumors. The initial trials are scheduled to begin at the University of Texas, M.D. Anderson Cancer Institute in Houston, and the University of Wisconsin's Comprehensive Cancer Center in Madison. The "molecular oncology" section of this protocol provides more detailed information about endostatin and angiostatin.
(To find out specific information about entering these clinical trials, you may call (800) 544-4440).
Cancer patients using cytotoxic chemotherapy drugs should ask their oncologists to place them on FDA-approved immunoprotective drugs 1 week before the first chemotherapy drug is administered. Depending on the type of cancer and the chemotherapy regimen that will be used, two of the most important FDA-approved drugs to consider are Neupogen, a granulocyte-colony stimulating factor drug (G-CSF) and Leukine, a granulocyte-macrophage-colony stimulating factor (GM-CSF).
Neupogen and Leukine stimulate the production of T-lymphocytes, macrophages, and other immune cells which are valuable in preventing the toxic effects on the bone marrow during chemotherapy. These immune-protecting drugs enable chemotherapy to be given at a higher dose that may make it effective. Stimulated macrophages are powerful tumor killers, as has been demonstrated by clinical studies using interleukin-2 and GM-CSF, or G-CSF. In addition, colony growth factors are able to accelerate regeneration of blood cells following chemotherapy. Initial clinical experience with GM-CSF and G-CSF has shown that severe neutropenia (immune impairment) due to chemotherapy drugs may be prevented or at least decelerated, reducing the number of severe infections.
Alpha-interferon and interleukin-2 are immune cytokines (regulators) that should also be considered by cancer patients. Interferon directly inhibits cancer cell proliferation and has already been used in the therapy of hairy cell leukemia, Kaposi's sarcoma, and malignant melanoma. Interleukin-2 allows for an increase in the cytotoxic activity of Natural Killer (NK) cells. These drugs must be carefully administered by an oncologist, as they can produce temporary side effects.
Retinoic acid (vitamin A) analog drugs enhance the efficacy of some chemotherapy regimens and reduce the risk of secondary cancers. Ask your oncologist to consider prescribing vitamin A analog drugs such as Accutane. Again, the use and dosage of potentially toxic drugs such as Accutane must be carefully prescribed by your attending oncologist.
Some cancer patients produce too many T-suppressor cells that shut down optimal immune function. The administration of drugs such as cimetidine prevent cancer cells from prematurely shutting down the immune system. An immune cell subset blood test will reveal the status of your T-helper cells, T-suppressor cells, and natural killer cell count and activity.
The proper administration of Neupogen or Leukine prior to the initiation of chemotherapy can dramatically reduce the immune damage that chemotherapy inflicts on the body and increase the cancer cell killing efficacy of conventional chemotherapy drugs. Please remember that, so far, we have only talked about drugs that require physician administration. There are safe nutrients that can be self-administered that also protect against chemotherapy toxicity and immune impairment.
Some of these nutrients include Coenzyme Q10, which has been shown in several studies to protect against chemotherapy damage to the heart. CoQ10 was highlighted as the topic of professional medical discussion as a complementary treatment for cancer at a recent meeting (Oncology Hunting) 1999 Feb; 13 :166). Natural vitamin E succinate has also been shown to protect organs throughout the body from the damaging effects of cytotoxic chemotherapy.
CAUTION: Some studies indicate that Coenzyme Q10 should not be taken at the same time as chemotherapy. If this is true, it would be disappointing, since CoQ10 is so effective in protecting against adriamycin-induced cardiomyopathy. Adriamycin is a chemotherapy drug sometimes used as part of a chemotherapy cocktail. Until more research is known, it is not possible to make a definitive recommendation whether to take CoQ10 during chemotherapy.
Supplemental melatonin in doses of 10 to 40 mg a night can protect and restore normal blood-cell production caused by the toxicity of chemotherapy. A study was performed in 80 patients with metastatic solid tumors to evaluate the benefits of melatonin. Patients received either chemotherapy alone or chemotherapy plus 20 mg each night of melatonin. Thrombocytopenia was significantly less frequent in patients receiving melatonin. Other common side effects of cancer chemotherapy-such as malaise, asthenia, stomatitis, and neuropathy-occurred less frequently in patients receiving melatonin. This corroborated previous studies showing that the administration of melatonin during chemotherapy can prevent some side effects, especially myelosuppression (blood-cell production suppression) and neuropathy.
The administration of FDA-approved drugs such as Neupogen or Leukine are important to cancer patients, even though melatonin has similar mechanisms of action. There are too many published studies about the prophylactic benefits of these FDA-approved drugs for them not to be used prior to the administration of chemotherapy.
To treat low white blood cell counts, the FDA-approved drug Neupogen or Leukine may be considered by your immunologist or hematologist. Drugs such as Neupogen, Leukine, and Intron A alpha-interferon (an immune-modulating cytokine) can restore immune function debilitated by toxic cancer chemotherapy drugs. In one study, patients with refractory (resistant to treatment) solid tumors treated with standard chemotherapy and GM-CSF had a 33.3% objective response rate, versus 15% with chemotherapy alone. If you are on chemotherapy and your blood tests show immune suppression, you should demand that your oncologist use the appropriate immune restoration drug(s).
(Please refer to the Cancer Chemotherapy protocol for additional suggestions on protecting against the multiple toxicities these drugs can cause.)
Cancer patients whose tumor cells have a mutant p53 oncogene are far more likely to benefit from certain therapies than are others. Only a pathology examination of the actual cancer cells can determine p53 status. An immunohistochemistry test can help to determine the p53 and RAS oncogene status of tumor cells. The following laboratory can perform this test:
1010 Third Avenue, Suite 203
New York, N.Y. 10021
Phone: 1 (800) 447-5816
IMPATH Laboratories measures mutant p53. If the test is positive, you have mutant p53 and are more likely to benefit from products such as soy genistein. If the test is negative, it indicates that you have functional p53 and are less likely to benefit from soy extracts.
The Life Extension Foundation first recommended immunohistochemistry testing in 1997. An article that appeared in a September 1999 issue of the Lancet (1999; 354:896-900) showed that immunohistochemical detection aids in the diagnosis and staging of breast cancer and should become "a standard method of node examination in postmenopausal patients." While the Lancet study looked only at breast cancer cells, the Foundation continues to recommend that all cancer patients consider immunohistochemical testing of their tumor cells to determine p53, RAS, and other oncogene status
With one in three Americans now using alternative medicine therapies regularly, many conventional oncologists are still not incorporating the published findings of nutritional science that benefit their patients' fight against cancer.
The Life Extension Foundation has researched an impressive collection of published studies showing that the disease process can be favorably mitigated with nutritional factors. These adjuvant treatments present approaches to boost immune system function, inhibit cancer cell division, induce cancer cells to differentiate back into mature cells, inhibit cancer cell metastases, prevent angiogenesis, and modulate the effect of hormones on cancer cell growth. These studies also reveal complementary methods for reducing the toxicity and the suppression of the immune system for both chemotherapy and radiation therapy.
It is impossible to completely describe all the mechanisms of action for the nutrients and hormones recommended in this Cancer Treatment protocol. What follows are discussion and studies that substantiate key recommendations of the protocol. The inclusion of certain nutrients in the following descriptions does not mean that they are more important than nutrients such as vitamin C and selenium, which are not discussed because of lack of space.
Many cancers require aggressive conventional therapies. The Life Extension Foundation has not found an effective alternative therapy that is sufficiently potent to shrink large primary or widely disseminated cancer. Treatment of such advanced tumors may yet require conventional therapies such as chemotherapy, radiation therapy, and surgery. The conventional approach to cancer using one or more of the big three can leave the patient's immune system suppressed and can induce a catabolic (or wasting) state with rapid weight loss. Cancer patients should insist that their oncologists accept their desire to support their immune systems with nutritional therapies and the benefits of using such protocols to assist the conventional medicine.
The Foundation emphasizes the importance of regular tumor marker testing to measure and monitor cancer status and therapy. Patients should establish with their doctors a planned schedule for cancer testing to monitor their progress during treatment. Modern testing is one of the most important tools for combating cancer, and both the patient and the doctor should be cognizant of the latest testing methods and should establish a monthly or regular testing schedule. Some cancers will require x-ray, MRI, or CAT scans to be detected and/or monitored, while other cancers can be monitored using blood tumor markers. For cancers that do not have an established blood tumor marker test, patients should use MRI, CAT scans, and other imaging diagnostics every 30 to 60 days to determine whether tumor shrinking is actually occurring and to measure the progress of any remissions seen.
Patients who have been diagnosed with large primary tumors may have to rely on conventional cancer therapy to treat the primary tumor, however, the nutrient and hormone adjuvant therapies presented in this book may help control metastasized cancer cells and reduce the toxicity of chemotherapy and radiation therapy. It should be noted that nutritional therapy is a long-term therapy requiring consistent and proper use of nutritional supplements and the measuring of cancer status (via regular blood testing) to determine the patient's response. The use of nutritional support is gaining in popularity because of high public demand and scientific findings.
Chemotherapy has a poor overall record of success over the past 30 years, but the Life Extension Foundation has identified adjuvant therapies to augment chemotherapies by making these drugs less toxic to healthy cells and more toxic to cancer cells, and by reducing the suppression of the immune system.
It should be noted that many cancer patients turn to alternative therapy fairly late in the course of the disease. Under such circumstances, and after the failure of conventional medicine, the prognosis for a cure is poor and the best many patients can hope for is an increased survival rate and reduced pain. In many cases, the failure of alternative medicine at the latest stages of cancer is used as a political statement by the medical establishment on the general topic of alternative therapies for cancer therapy. Keep in mind that conventional medicine has, in most cases, failed to offer any improvement or hope for the majority of desperate patients with advanced-stage cancers.
Finnish oncologists used high doses of nutrients along with chemotherapy and radiation for lung cancer patients. Normally, lung cancer is a "poor prognostic" malignancy advanced with a 1%-2% expected survival at 30 months under normal treatment. In this study, however, 8 of 18 patients (44%) were still alive 6 years after therapy.
Oncologists at West Virginia Medical School randomized 65 patients with transitional cell carcinoma of the bladder into either the "one-per-day" vitamin supplement providing the RDA, or a group which received the RDA supplement plus 40,000 IU of vitamin A, 100 mg of B6, 2000 mg of vitamin C, 400 IU of vitamin E, and 90 mg of zinc. At 10 months, tumor recurrence was 80% in the control group (RDA supplement) and 40% in the experimental "megavitamin" group. Five-year projected tumor recurrences were 91% for controls and 41% for "megavitamin" patents. Essentially, high-dose nutrients cut tumor recurrence in half.
In a nonrandomized clinical trial, Drs. Hoffer and Pauling instructed patients to follow a reasonable cancer diet (unprocessed food low in fat, dairy, and sugar), coupled with therapeutic doses of vitamins and minerals. All 129 patients in this study received concomitant oncology care. The control group of 31 patients who did not receive nutrition support lived an average of less than 6 months. The group of 98 cancer patients who did receive the diet and a supplement program was categorized into three groups:
Poor responders or approximately 20% of treated group. These had an average lifespan of 10 months or a 75% improvement over the control group.
Good responders, or approximately 47%, who had various cancers including leukemia, lung, liver, and pancreas; had an average lifespan of 72 months (6 years).
Good female responders or approximately 32% with involvement of reproductive areas (breast, cervix, ovary, uterus); group 3 had an average lifespan of over 10 years. Many were still alive at the end of the study.
In examining the diet and lifespan of 675 lung cancer patients over the course of 6 years, researchers found that the more vegetables consumed, the longer the lung cancer patient lived.
In 200 cancer patients studied who experienced "spontaneous regression," 87% made a major change in diet, mostly vegetarian in nature, 55% used some form of detoxification, and 65% used nutritional supplements.
Researchers at Tulane University compared survival in patients who used the macrobiotic diet versus patients who continued with their standard western lifestyle. Of 1467 pancreatic patients who made no changes in diet, 146 (10%) were alive after one year, while 12 of the 23 matched pancreatic patients (52%) consuming macrobiotic foods were still alive after one year.
Genistein has shown significant cell-inhibiting effects in many different types of cancer. A study was conducted to examine the role genistein played in growth factors'-such as protein tyrosine kinase and in thymidine incorporation into cancer cells. Genistein suppressed protein tyrosine kinase activity and the subsequent growth stimulatory incorporation of thymidine into cancer cells. The scientists speculated that genistein has potential value in the prevention and treatment of some tumors in vivo.
In other studies, genistein has shown anti-angiogenesis properties, cancer cell adhesion-inhibition properties, estrogen-receptor blocking properties, and apoptosis-inducing effects. An investigation into the effect of soy genistein on the growth and differentiation of human melanoma cells showed that genistein significantly inhibited cell growth. Some studies suggest that genistein may enhance the efficacy of certain chemotherapy regimens.
Soy protein contains several anticancer agents including genistein and other isoflavones. In one study, a lower incidence of prostate cancer was shown in Chinese men who had higher amounts isoflavonoid phytoestrogens, daidzein, and equol within their prostatic fluids and in their blood plasma. The study concluded that the high concentrations of isoflavones present in the prostatic fluid of Asian men may protect them from prostate disease.
A study in a 1999 issue of the Journal of Nutrition reported that "dietary soy products may inhibit prostate tumor growth through a combination of direct effects on tumor cells and indirect effects on tumor neovasculature." Earlier in 1999, a study in the British Journal of Cancer reported an inhibitory effect of genistein and quercetin on the growth of tumors.
Curcumin and genistein have both been shown to inhibit the growth of estrogen-positive human breast cancer cells induced by pesticides. When curcumin and genistein were added to breast cancer cells, a synergistic effect resulted in a total inhibition of cancer cell growth caused by pesticide-induced estrogenic activity. This study suggested that the combination of curcumin and genistein in the diet has the potential to reduce the proliferation of estrogen-positive cells induced by mixtures of pesticides or estrogen. Since it is difficult to remove pesticides completely from the diet, and since neither curcumin nor soy genistein is toxic to humans, their inclusion in the diet in order to prevent hormone-related cancers deserves consideration. Curcumin appears to function via several different mechanisms to inhibit cancer cell proliferation.
Differentiation-inducing agents such as genistein, retinoids, and vitamin D analogs inhibited tumor cell-induced angiogenesis in vitro and in vivo. Simultaneous administration of retinoids and 1,25-dihydroxy vitamin D3 led to a synergistic inhibition of tumors associated with angiogenesis in mice. Recently, these compounds have been shown to induce and act in concert with natural angiogenic inhibitors such as interferons.
A study was conducted to determine whether genistein could induce human breast adenocarcinoma cell maturation and differentiation. Treating these cells with genistein resulted in growth inhibition accompanied by increased cell maturation. These maturation markers were optimally expressed after 9 days of treatment with genistein. Both estrogen-receptor-positive and estrogen-receptor-negative cells became differentiated in response to genistein, which is a crucial step in inducing cancer cell apoptosis (programmed cell death). Despite this study, we do not recommend that women with estrogen-receptor-positive breast cancer use soy genistein because of the following evidence.
Genistein appears to be especially effective against prostate cancers. One study showed that genistein inhibited the proliferation and expression of the in vitro invasive capacity of tumoral prostatic cells. In a cell culture system, genistein appeared to be cytotoxic and inhibitory to PC-3 cells. The more aggressive the prostate cancer cell culture studies, the more effective was the genistein, both with respect to proliferation rate and inhibition of growth factors.
More recently, the Japanese Journal of Cancer Research (1999 April; 90 :393-98) reported results of a comprehensive rat study which provides further evidence that soybean isoflavones have a potential as chemopreventive agents against carcinogenesis in the prostate.
Other investigators have reported anticancer effects of genistein on lung cancer in the 1999 Journal of Nutritional Cancer, where researchers reported a specific effect on lung cancer cells.
Breast Cancer and Genistein
One study tested the effects of naturally occurring flavonoids on the proliferation of an estrogen-receptor-positive human breast cancer cell line. Genistein inhibited cell proliferation, but this effect was reversed when estrogen was added. The flavonoids hesperidin, naringenin, and quercetin inhibited breast cancer cell proliferation even in the presence of high levels of estrogen. These flavonoids apparently exert their antiproliferative activity via a mechanism that is different from that of genistein. Women with any type of breast cancer should test their serum estrogen levels to make sure that too much estrogen is not present if they are taking high doses of soy. Estrogen can combine with the phytoestrogen genistein to cause some breast cancer cells to grow faster. Other studies, however, show that genistein blocks certain types of estrogen receptor sites, thus inhibiting the proliferation of these types of breast cancer cells.
CAUTION: The Foundation has made a preliminary determination that women with estrogen-receptor-positive breast cancer should not take soy supplements based on evidence that an estrogenic growth effect could occur in some forms of estrogen-receptor-positive breast cancer. Until more is known about the effects of soy phytoestrogens in this type of cancer, compounds such as genistein should be avoided in those with estrogen-receptor-positive breast cancer.
Summing up the possible benefits of genistein and other natural therapies is a May 1999 study in the North American Urological Clinical Journal regarding findings of new nontoxic cancer therapies. Researchers reported, "Other agents that promise low toxicity include vitamin D and its analogs, genistein and related isoflavones, green tea polyphenols, and retinoic acid analogs."
Information on how cancer patients should use soy genistein appears at the end of this protocol. The Foundation reiterates that regular testing is recommended for all cancer patients to measure the status and progression of the cancer and the trend of any protocol used; i.e., if tumor markers elevate for 30 to 60 days after beginning soy extract supplementation, discontinue use and seek another therapy immediately.
Green tea is the staple beverage of the Japanese and Chinese cultures. It contains a chemical known as epigallocatechin gallate, which is one of the polyphenolic catechins, a family of chemicals many times more potent against free radicals than vitamin E. In a study to measure the effect of green tea consumption in Japanese populations, it was found that green tea had a "preventative effect against cancer among humans." This study surveyed 8552 people over a 9-year period (71,248 person years) and found that cancer incidence was low for those people who consumed green tea regularly. The study also found that the more green tea was consumed, the lower the risk of cancer. Many women interviewed for the study consumed more than 10 cups of green tea daily, and their cancer incidence was the lowest in the study. The overall consumption of green tea correlated with both men and women.
University Hospitals of Cleveland researchers reported in the May 1999 Journal of Urological Oncology that prostate cancer (PC) is the second leading cause of cancer-related deaths among males in the United States. According to an estimate, 1 of every 11 American men will eventually develop PC. Researchers suggested that one way to reduce the occurrence of cancer is through natural chemoprevention. PC represents an excellent candidate disease for chemoprevention because it is typically diagnosed in men over 50 years of age, and therefore even a modest delay in neoplastic development achieved through pharmacological or nutritional intervention could result in a substantial reduction in the incidence of clinically detectable disease. The ideal agent(s) suitable for chemoprevention of PC should be the one(s) with proven efficacy in the laboratory experiments on one hand, and with proven epidemiological basis on the other hand. This review attempts to address the issue of possible uses of tea, especially green tea, for the prevention of PC.
The researchers provided an experimental as well as an epidemiological basis for this possibility. They also pointed out that many laboratory experiments conducted in cell culture systems and in animal models have shown the usefulness of green tea and the polyphenols present in it-against PC.
The epidemiological basis for this possibility is twofold. First, some epidemiological observations have suggested that people who consume tea regularly have a lower risk of PC-related deaths. Second, the incidence of PC in China, a population that consumes green tea on a regular basis, is the lowest in the world (Semin. Urol. Oncol., 1999 May; 17 :70-76).
Another study reported in the July 1999 Japanese Journal of Cancer Research further substantiated the benefits of green tea against specific cancer cells. Researchers emphasized its role in the prevention and treatment of cancers such as stomach cancer.
Investigators reported in the September 1999 American Journal of Clinical Nutrition that "herbal teas inhibit mevalonate synthesis and thereby suppress cholesterol synthesis and tumor growth," further supporting the section in this protocol which discusses the reduction of cholesterol in the fight against cancer (Am. J. Clin. Nutr., 1999 Sept; 70 [3 Suppl]:491S-99S).
A study found that apoptosis occurred in prostate cancer cell lines LNCaP, PC-3, and DU125 in response to green tea extract. The cancer cell morphology and DNA fragmentation were induced by the most active constituent of green tea, epigallocatechin gallate (EGCG). The study concluded that EGCG triggered apoptosis (programmed cell death) in human prostate cancer cells.
Another study found that two phenols contained in green tea extract had inhibitory effects on several cancer cell lines including lung, stomach, and mammary cancers. It was found that the phenols, epigallocatechin (EGC), and epicatechin gallate (ECG) inhibited the growth of human lung cancer cell PC-9.
Collectively, the results indicate
that tea possesses anticarcinogenic activity in the colon, and this most likely
involves multiple inhibitory mechanisms (Proc. Soc. Exp. Biol. Med.,
1999 April; 220 :239-43).
A review published in a 1999 issue of Experimental Biological Medicine summarizes the mechanisms of action of green teas as follows:
Epidemiological studies in China have provided reasons to suspect that a rich garlic content in the diet might reduce the proliferation of tumors in humans. Researchers reported in the March 1999 issue of Phytomedicine relative to experiments conducted on human tumor cell lines to determined the influence of garlic to inhibit the growth of human liver or colon cancer cell lines. Results suggest a strong antiproliferative effect of garlic on human cancer cells (Phytomedicine, 1999 Mar; 6 :7-11).
Although the herb garlic by itself possesses these medical properties, aged garlic extract (AGE) has additional benefits due to tightly controlled manufacturing. The process of cold-aging garlic may enhance its medicinal factors, and the aging process also reduces the tendency of garlic to irritate the digestive tract.
A study investigated aged garlic extract in an effort to determine whether it could inhibit proliferation of cancer cells. The proliferation and viability of erythroleukemia and hormone-responsive breast and prostate cancer cell lines were evaluated. The erythroleukemia cells were not significantly affected by the garlic extract, but the breast and prostate cancer cell lines clearly were susceptible to the growth-inhibitory influence of aged garlic extract. The antiproliferative effect of aged garlic extract was limited to actively growing cells. This study provided evidence that garlic can exert a direct effect on established cancer cells.
A Chinese study revealed that garlic effectively prevented oral precancer and oral cancer cell proliferation (Hunan I Ko Ta Hsueh Hsueh Pao, 1997; 22 :246-48).
There is a debate among alternative doctors as to whether aged "odorless" garlic is better than high-allicin garlic supplements. For those fighting cancer on an acute basis, perhaps both forms of garlic should be considered. Specific garlic dosing suggestions are provided at the end of this protocol.
Nutrients with an inhibitory effect on cancer-cell proliferation include vitamin A (and synthetic vitamin A analogs). The best example of the effectiveness of vitamin A and beta-carotene in inhibiting cell proliferation is with patients who suffer from cancer of the mouth. Vitamin A or beta-carotene supplementation may induce a remission in early stage I mouth cancer as long as these nutrients continue to be consumed. A similar study of 44 patients with mouth lesions caused by chewing tobacco found that spirulina's (chlorella) high concentration of beta-carotene also proved effective for 20 patients after one year.
Vitamin D3 and its analogs may inhibit cancer cell growth and induce cancer cells to differentiate back into normal cells. An experimental study was performed on a prostate cancer cell line, PC-3, to measure the effect of a vitamin D analogue. A control medium was conducted in parallel. Cell proliferation was measured at 7 and 12 days, and it was found that results "were dose dependent varying from 40 to 70% of controls." The maximum inhibitory effect was at 0.1 micromol/L; however, the study found that "longer incubation times" were more effective than high concentrations of the vitamin D analog. The study concluded that vitamin D deficiency increased the risk of prostate cancer.
The vitamin D analog was used in another study of MCF-7 breast cancer cells grafted into nude mice to determine whether vitamin D could mediate apoptosis of breast cancer in vivo. Two delivery methods were used to administer the vitamin D time release pellets and daily injections. At 4 weeks the volume of tumors was reduced fourfold versus the control group. Characteristic "apoptotic morphology" was observed at 5 weeks with MCF-7 tumor cells showing a sixfold increase in DNA fragmentation measured by in situ labeling. The study found that vitamin D demonstrated apoptotic morphology and regression of human breast tumors and that the study "supported the concept that vitamin D compounds can effectively target human breast cancer."
CAUTION: Both vitamin A and vitamin D can have toxic effects in high doses. Consult with health care professionals before increasing doses of either vitamin to high levels.
Fish oil may enhance the effectiveness of cancer chemotherapy drugs. A study compared different fatty acids on colon cancer cells to see whether they could enhance mitomycin C, a chemotherapy drug. The fish oil containing high amounts of eicosapentaenoic acid (EPA) was shown to sensitize colon cancer cells to mitomycin C. Fish oil has been shown to specifically induce apoptosis of pancreatic cancer cells and to inhibit metastasis of breast and lung cancer cells.
A June 1999 study demonstrated the benefits of EPA in reducing acute protein phase response which leads to wasting in cancer patients. Researchers indicated that "the presence of an acute-phase protein response has been suggested to shorten survival and contribute to weight loss in patients with pancreatic cancer. The acute-phase protein response tends to progress in untreated patients but may be stabilized by the administration of a fish oil-enriched nutritional supplement. This may have implications for reducing wasting in such patients" (Journal of Nutrition, 1999 June; 129(6):1120-25).
Other studies have found that EPA induced alternations of the fatty-acid composition of cancer cells, which made them more vulnerable to the chemotherapy effects. Although preliminary, these findings imply that EPA specifically enhances the chemosensitivity of malignant cells.
CLA has been shown both in vitro and in animal models to have strong antitumor activity. An early protective effect was noted in one study that focused on the maturation of mammary cells, and the study concluded that "exposure to CLA during Y-maturation may modify the development of Y-target cells that are normally susceptible to carcinogen-induced transformation."
Investigators at Roswell Park
Cancer Institute in Buffalo, New York, conducted rat studies and reported
inhibited breast cancer cell outgrowth using CLA (Exp. Cell. Res., 1999
July 10; 250 :22-34).
Another study investigated the effect of dietary CLA on the growth of human breast adenocarcinoma cells in immunodeficient mice. Similarly it was found that CLA inhibited the development and growth of mammary tumors. Moreover, CLA completely abrogated the spread of breast cancer cells to lungs, peripheral blood, and bone marrow. These results indicate the ability of dietary CLA to block both the local growth and systemic spread of human breast cancer via mechanisms independent of the host immune system.
CLA has been shown to inhibit initiation and promotion stages of carcinogenesis in several experimental animal models. A study of mice with skin tumors showed that CLA inhibited tumor yield. This study confirmed previous studies showing that CLA inhibits tumor promotion in a manner that is independent of its cancer-prevention effects.
The popularity of echinacea has grown during the last couple of years because of its ability to enhance the immune system, especially during the cold and flu season. However, echinacea also has profound anticancer effects related to its ability to increase NK cell activity, which was improved by 221% in one study of patients suffering from metastasized cancers of the colon and esophagus. Another naturally occurring chemical found in echinacea (arabinogalactan) is known to stimulate macrophages' B tumor killing cells.
Benefits Whey Protein
Whey protein concentrate has been studied for cancer prevention and treatment. When different groups of rats were given a powerful carcinogen, those fed whey protein concentrate showed fewer tumors and a reduced pooled area of tumors. The researchers found that whey protein offered "considerable protection to the host" over that of other proteins, including soy.
At low concentrations, whey appears to inhibit the growth of breast cancer cells. One clinical study with cancer patients showed a regression in some patients' tumors when they were fed whey protein concentrate at 30 grams per day. As noted in a related protocol (but worth repeating in this context), this discovery led researchers to discover a relationship between cancerous cells, whey protein concentrate, and glutathione. Glutathione is an antioxidant that protects the body against harmful compounds. It was found that whey protein concentrate selectively depletes cancer cells of their glutathione, thus making them more susceptible to cancer treatments such as radiation and chemotherapy.
It has been found that cancer cells and normal cells will respond differently to nutrients and drugs that affect glutathione status. What is most interesting is that the concentration of glutathione in tumor cells is higher than that of the normal cells that surround it. This difference in glutathione status between normal cells and cancer cells is believed to be an important factor in cancer cells' resistance to chemotherapy. As the researchers put it, "Tumor cell glutathione concentration may be among the determinants of the cytotoxicity of many chemotherapeutic agents and of radiation, and an increase in glutathione concentration in cancer cells appears to be at least one of the mechanisms of acquired drug resistance to chemotherapy."
They further state, "It is well known that rapid glutathione synthesis in tumor cells is associated with high rates of cellular proliferation. Depletion of cancer cell glutathione in vivo decreases the rate of cellular proliferation and inhibits cancer growth." The problem is, it's difficult to reduce glutathione sufficiently in tumor cells without placing healthy tissue at risk and putting the cancer patient in a worse condition. What is needed is a compound that can selectively deplete the cancer cells of their glutathione while increasing, or at least maintaining, the levels of glutathione in healthy cells. This is exactly what whey protein appears to do.
This research found that cancer
cells subjected to whey proteins were depleted of their glutathione, and their
growth was inhibited, while normal cells had an increase in glutathione and
increased cellular growth. These effects were not seen with other proteins. Not
surprisingly, the researchers concluded, "Selective depletion of tumor
cell glutathione may in fact render cancer cells more vulnerable to the action
of chemotherapy and eventually protect normal tissue against the deleterious
effects of chemotherapy." The exact mechanism by which whey protein
achieves this is not fully understood, but it appears that it interferes with
the normal feedback mechanism and regulation of glutathione in cancer cells. It
is known that glutathione production is negatively inhibited by its own
synthesis. Since baseline glutathione levels in cancer cells are higher than
those of normal cells, it is probably easier to reach the level of
negative-feedback inhibition in the cancer cells' glutathione levels than in
the normal cells' glutathione levels.
(See the Benefits of Whey Protein section of the Cancer Chemotherapy protocol.)
The evidence continues to mount that melatonin may be an effective adjuvant cancer therapy because melatonin boosts immune system function, suppresses free radicals, inhibits cell proliferation, and helps to change cancer cells back into normal cells.
A randomized study of 70 patients with advanced nonsmall lung cancer was conducted using chemotherapy (cisplatin) and melatonin support to measure immune system improvement during chemotherapy. The study was conducted using the World Health Organization specifications for clinical response and toxicity, and it was found that "chemotherapy was well tolerated in patients receiving melatonin and, in particular, the frequency of myelosuppression, neuropathy, and cachexia was significantly reduced in the melatonin group." The study concluded that chemotherapy with 20 mg daily of melatonin may improve the chemotherapy particularly with respect to the patient's survival time and the mitigating effect of "chemotherapeutic toxicity" for patients with advanced non-small cell lung cancer. This same hospital facility conducted a melatonin survey (several different but related cancer studies using the same dosage of melatonin = 20 mg/daily) that found similar results for patients being treated with the chemotherapy drugs mitoxantrone, cisplatin, etoposide, and 5-fluorouracil.
A 1999 Slovak research study regarding the use of melatonin in the treatment of tumors reported that "melatonin has potentially important influence on the neoplastic growth and direct and indirect oncostatic effect in some forms of neoplasia. The beneficial influence of melatonin alone or its combination with immunotherapy, radiotherapy, or chemotherapy in many clinical studies in patients with tumors was demonstrated" (Cesk. Fysiol., 1999 Feb; 48 :27-40).
Another 1999 study in the Mutagenesis Cancer Journal (1999 Jan; 14 :107-12) confirmed that melatonin is able to modulate and reduce chromosome damage by its involvement in regulating adverse oxidative stress and processes, thereby reducing DNA damage. In particular, researchers reported that melatonin is able to decrease damage at the chromosomal level.
Melatonin has been seen to enhance the anti-cancer action of interleukin-2 (IL-2) and to reduce IL-2 toxicity. Melatonin use in association with IL-2 cancer immunotherapy has been shown to have the following actions:
The subcutaneous administration of 3 million IU a day of interleukin-2 (IL-2) and high doses of melatonin (40 mg a day orally) in the evening has appeared to be effective in tumors resistant either to IL-2 alone or to chemotherapy. The dose of 3 million IU a day of interleukin-2 is a low dose, while serious toxicity normally begins at 15 million IU a day. At present, 230 patients with advanced solid tumors and life expectancy less than 6 months have been treated with this melatonin/IL-2 combination. Objective tumor regressions were experienced in 44 patients (18%), mainly in patients with lung cancer, hepatocarcinoma, cancer of the pancreas, gastric cancer, and colon cancer. A survival longer than one year was achieved in 41% of the patients. The preliminary data show that melatonin synergizes with tumor necrosis factor (TNF) and alpha-interferon by reducing their toxicity.
Indole-3-carbinol (I3C), isothiocyanate, and sulforaphane are phytochemicals found in cruciferous vegetables. They have an inhibitory effect on cancer cell proliferation.
Sprague-Dawley rats were subjected to 7,12-dimethylbenzanthracene-(DMBA) induced mammary tumors in a study to report on antitumorigenic activity of di-indolylmethane (DIM), an acid B catalyzed metabolite of I3C that is formed in the intestines. The study found that DIM inhibited the proliferation of MCF-7 cells and that DIM (at 5 mg/kg every other day) inhibited the mammary tumor growth induced by DMBA. The study concluded that DIM metabolized from the phytochemicals of cruciferous vegetables presents a new class of relatively nontoxic Y antiestrogens that inhibit E2-dependence without affecting normal cells.
A position paper from the American College of Physicians published in 1989 basically stated that total parenteral nutrition (TPN) had no benefit on the outcome of cancer patients. Unfortunately, this article excluded malnourished patients, which is bizarre, since TPN only treats malnutrition, not cancer. Most of the scientific literature shows that weight loss drastically increases the mortality rate of most types of cancer, while also lowering the response to chemotherapy. Chemotherapy and radiation therapy are sufficient biological stressors to induce malnutrition by themselves.
In the early years of oncology, it was thought that one could starve the tumor out of the host. Pure malnutrition (cachexia) is responsible for at least 22% and up to 67% of all cancer deaths. Up to 80% of all cancer patients have reduced levels of serum albumin, which is a leading indicator of protein and calorie malnutrition. Dietary protein restriction in the cancer patient does not affect the composition or growth rate of the tumor, but does restrict the patient's well being.
Parenteral feeding improves tolerance to chemotherapeutic agents and immune responses. One study indicated that malnourished cancer patients who were provided TPN had a mortality rate of 11%, while the group without TPN feeding had a 100% mortality rate. Preoperative TPN in patients undergoing surgery for GI cancer provided general reduction in the incidence of wound infection, pneumonia, major complications, and mortality. Patients who were the most malnourished experienced a 33% mortality and 46% morbidity rate, while those patients who were properly nourished had a 3% mortality rate with an 8% morbidity rate.
In 20 adult hospitalized patients on TPN, the mean daily vitamin C needs were 975 mg/day, which is over 16 times the RDA. Of the 139 lung cancer patients studied, most tested deficient or scorbutic (clinically vitamin-C deficient). Another study of cancer patients found that 46% tested scorbutic while 76% were below acceptable levels for serum ascorbate. Experts now recommend the value of nutritional supplements, especially in patients who require prolonged TPN support. Remember that 40% or more of cancer patients actually die of malnutrition, not from the cancer, according to medical experts. Nutrition therapy is the only treatment for malnutrition.
Properly nourished patients experience less nausea, malaise, immune suppression, hair loss, and organ toxicity than patients on routine oncology programs. Antioxidants such as beta-carotene, vitamin C, vitamin E, and selenium appear to enhance the effectiveness of chemotherapy, radiation, and hyperthermia while minimizing damage to the patient's normal cells. Protecting healthy cells thus makes these conventional therapies more of a "selective toxin."
An optimally nourished cancer patient can better tolerate the rigors of cytotoxic therapy. While, in simplistic theory, vitamin K might inhibit the effectiveness of anticoagulant therapy (Coumadin), vitamin K actually seems to augment the antineoplastic activity of Coumadin. In a study with human rheumatoid arthritis patients being given methotrexate, folic acid supplements did not reduce the antiproliferative therapeutic value of methotrexate. Tumor-bearing mice fed high doses of vitamin C (antioxidant), along with the pro-oxidant chemotherapy drug adriamycin, had a prolonged life and no reduction in the tumor-killing capacity of adriamycin. Lung cancer patients who were provided antioxidant nutrients prior to, during, and after radiation and chemotherapy had enhanced tumor destruction and significantly longer lifespan. Some of the benefits of complimentary nutrition therapy include the following:
Nobel laureate Otto Warburg, Ph.D., discovered in 1955 that cancer cells primarily use glucose for fuel, with lactic acid being an anaerobic by- product. Lactic acid buildup then generates a lower pH, fatigue, and enlarged liver (where lactic acid is converted back to pyruvate in the Cori cycle). Cancer causes a breakdown in normal energy metabolism, which is one of the reasons why so many cancer patients die of malnutrition or cachexia.
Since Warburg's pivotal study was published in a 1956 issue of the journal Science, other research has shown that the glucose utilization rate is high in neoplastic tissues. Glucose is, in fact, the preferred energy substrate for cancer cells, utilized mainly via the anaerobic glycolytic pathway. The large amount of lactates produced by this process is then transported to the liver where it is converted to glucose, thus contributing to further increase the host's energy wasting.
Interfering with carbohydrate and/or energy metabolisms could preferentially impair the malignant cells. Studies show that in vivo consumption of glucose by neoplastic tissues is very high. It is well known that the brain is one of the highest consumers of glucose among the normal tissues. Hepatomas and fibrosarcomas have been shown to consume roughly as much glucose as the brain does, and more prevalent carcinomas consume about twice as much.
One study showed lactate levels to be 27 to 83% higher in cancer patients than in related controls. If cancer cells use glucose through anaerobic fermentation, then lactic acid must accumulate as the inefficient by-product of energy metabolism. Hence, cancer therapies need to take into consideration the importance of regulating blood glucose levels.
Another study on ten healthy human volunteers assessed fasting blood glucose levels and the phagocytic index of neutrophils. Glucose, fructose, sucrose, honey, and orange juice all significantly decreased the capacity of neutrophils to engulf bacteria as measured by the slide technique. Starch ingestion did not have this effect. One epidemiological study showed that the risk associated with the intake of sugars, independent of other energy sources, more than doubled for biliary tract cancer in older women. Other studies show a correlation between breast cancer mortality and sugar consumption.
In his book Beating Cancer with Nutrition, Dr. Patrick Quillin makes specific recommendations about how glucose modulation can be utilized to help the cancer patient. Some of his recommendations include
Dr. Quillin provides a compelling case for the role of glucose in the growth and metastasis of cancer cells. According to Dr. Quillin, a frequent characteristic of many tumors is a high rate of glucose consumption along with an increase in anaerobic glycolysis (the conversion of glucose to lactase). By manipulating glucose levels, cancer cells can be starved over an extended time, or, conversely, glucose can be injected into the patient when a therapy is being utilized that targets rapidly dividing cells.
Glucose modulation therapy is an underutilized component in the treatment of cancer. There is not sufficient space in the protocol to discuss the complete aspects of glucose modulation therapy, but this is described in detail in Dr. Quillin's book, Beating Cancer with Nutrition. You can order it directly from the publisher by calling (918) 495- 1137. (The cover price is $14.95.)
The Foundation's Adjuvant Cancer Treatment Protocol is for most forms of cancer. This protocol assumes that the patient's primary tumor has been eradicated, at least partially, by surgery or by some other treatment. However, it may be followed even if the primary tumor has not yet been eradicated. The following is a step-by-step treatment plan.
These blood tests must be taken on a regular basis under the supervision of a physician in order to follow scientifically the Foundation's Cancer Treatment Protocol. It's the best way of knowing whether what you are taking is working and/or whether significant toxicity is developing. This is no time to guess! Since you will be having these tests performed monthly, you should price-shop for the best deal. The Life Extension Foundation offers these tests at discount prices, but if you have health insurance, it would save you money in the long run to have these tests performed by your physician.
Here are some accepted blood tumor markers for common cancers:
Type of Cancer
Tumor Marker Blood Test
PSA and prolactin
CA 27.29, CEA, alkaline phosphatase and prolactin (some doctors use the CA 15-3 in place of the CA 27.29)
Colon, rectum, liver, stomach and other organ cancers
CA 19.9, CEA, GGTP
Leukemia, lymphoma, and Hodgkin's disease
CBC with differential, immune cell differentiation and leukemia profile
CEA, CA 125, alkaline phosphatase PT, PTT and D-Dimer of fibrin
If the immune system is weakened enough, cancer cells can survive and multiply. The most critical part of the immune system is the thymus gland, a small organ just below the breast bone that governs the entire system. There are several products that promote healthy thymic activity.
Thymex is a product used by alternative physicians to stimulate immune function. It provides extracts of fresh, healthy tissue from the thymus and other glands that produce the disease-fighting cells of our immune system. The primary ingredient in Thymex is immunologic tissue from the thymus gland. Also included in Thymex is tissue from the lymph nodes and spleen that produces the white blood cells that engage in life-or-death combat with invading organisms in our bloodstream under the "instruction" of the thymus gland. Thymex is a synergistic formula that contains herbal activators and a full complement of natural homeopathic nutrients, in addition to fresh, healthy thymus, lymph, and spleen tissues. Thymex is a professional formula normally dispensed through doctor's offices. Thymex has been used extensively to amplify the immune potentiating effect of DHEA replacement therapy. According to a physician most familiar with DHEA, thymus extract is required to obtain the immune system-boosting benefit of DHEA.
KH3. Cancer patients usually have elevated cortisol levels that can suppress immune function. Take 1 to 2 tablets of KH3 daily on an empty stomach first thing in the morning and 1 or 2 KH3 tablets in the mid-afternoon on an empty stomach to suppress the damaging effects of cortisol.
DHEA can also suppress dangerously high cortisol levels while boosting immune function via other mechanisms. Doctors usually prescribe at least 25 mg per day of DHEA for their male cancer patients and a minimum of 15 mg a day of DHEA for females. Your monthly or bimonthly DHEA-S and immune cell subset tests and tumor marker tests will determine whether DHEA is producing a beneficial effect. Do not use DHEA if you have prostate cancer or estrogen-sensitive breast cancer.
Melatonin boosts immune function via several mechanisms of action. It also exerts an inhibitory effect on cancer cell proliferation and induces the differentiation of cancer cells into normal cells. Melatonin should be taken every night in doses ranging from 3 to 40 mg.
CAUTION: Some doctors are under the impression that leukemia, Hodgkin's disease, and lymphoma patients should avoid melatonin until more is known about its effects on these forms of cancer. If melatonin is tried in these types of cancer, tumor blood markers should be watched closely for any sign that melatonin is promoting tumor growth.
Show your oncologist the information in this book regarding the use of the FDA-approved drugs interleukin-2 or interferon and melatonin. Studies document that low doses of interleukin-2 or alpha-interferon combined with high doses of melatonin (10 to 50 mg nightly) are effective against advanced, normally untreatable cancers. Ask your doctor to prescribe these agents:
This immune-boosting program should be adjusted if the immune cell subset test or tumor marker tests fail to show marked improvement in the patient's immune function. For example, if there are too many T-suppressor cells, 800 mg a day of the drug Tagamet (now available over the counter) can lower the T-suppressor cell activity. T-suppressor cells often are elevated in cancer patients, which prevents them from mounting a strong immune response to the cancer.
CAUTION: Monthly blood tests can help ascertain whether toxicity is occurring in response to these high doses of vitamin A. Do not take vitamin A if you have thyroid cancer or suffer severe thyroid deficiency. (Refer to the Avoiding Vitamin A Toxicity protocol)
CAUTION: For most cancers, the determining factor of whether soy may work is whether your cancer cells carry a mutated p53 tumor suppressor gene, or whether they carry functional p53. If functional p53 is present, then soy genistein will probably not work. In small-cell lung cancer, however, it was recently determined that genistein's growth-inhibiting effects were independent of p53 function. Only specialized tumor cell tests (immunohistochemistry) can determine the p53 status of your particular cancer. Estrogen-receptor-positive breast cancer patients should avoid high doses of genistein.
Cancer cells are aberrant, transformed cells that proliferate (divide) more rapidly than normal cells until they kill the patient. Inducing cancer cells to "differentiate" back into normal cells is a primary objective of cancer researchers.
Caution: Monthly blood testing is mandatory when taking high doses of vitamin A or vitamin D3.
There are drugs approved by the FDA that may be of enormous benefit to certain cancer patients. These drugs include COX-2 inhibitors, the "statins," retinoid analogs, the interferons, interleukin-2, and immune-protecting drugs such as Leukine. These drugs are described throughout this protocol and require a prescription from a knowledgeable and cooperative oncologist for safe administration.
There are also drugs approved in other countries that may be effective against certain cancers. These drugs are not discussed because the FDA routinely seizes these life-saving medicines, thus making consistent administration virtually impossible.
For the malnourished patient, low-glucose, total parental nutrition is a must from the beginning of therapy. Reducing intake of sugars appears to be especially important, because cancer cells use glucose as a primary substrate.
Step Eight-Call the Life Extension Foundation
If following the above protocols does not result in significant immune enhancement, improvements in blood tumor markers, tumor shrinkage, weight stabilization, and an overall improvement in well being within two months, please call the Life Extension Foundation at (800) 544-4440 or refer to this Web-site for other, more aggressive options. Life Extension Foundation can also provide the latest in cancer testing services.
The Science behind Life Extension's Cancer Protocol
The recommendations made in this protocol are based exclusively on published scientific studies. The Foundation continues to research new therapies to provide the most comprehensive database of information to support this cancer treatment protocol. For the latest findings about cancer treatment and the actual abstracts that substantiate these recommendations, please refer to this Web site.
Specific Cancer Protocols
The Life Extension Foundation currently publishes separate protocols for the more common forms of cancers. The following cancer protocols are available at the following links.
CAUTION: The following information is extremely technical. The cooperation of your oncologist is vital to most cancer patients who seek to use the following information in an attempt to save their lives.
Determining RAS Mutations
The family of RAS proteins plays a central role in the regulation of cell growth and integration of regulatory signals that govern the cell cycle and proliferation. Mutant RAS genes were among the first oncogenes described for their ability to transform cells to a cancerous phenotype. Mutations in one of three genes (H, N, or K-RAS) encoding RAS proteins have been intimately associated with unregulated cell proliferation and are found in an estimated 30% of all human cancers. The frequency of RAS mutations appears to depend upon the specific tumor type analyzed. For example, 90% of pancreatic carcinomas contain a mutated oncogenic RAS protein, whereas RAS mutations are rarely found in breast carcinomas.
Approximately one third of liver cancers harbor a mutated RAS oncogene. Pravastatin, an inhibitor of the rate-limiting enzyme of cholesterol synthesis, inhibits growth of liver cancer cells. One of the possible mechanisms of pravastatin inhibition of cell growth is that pravastatin may inhibit the activity of RAS proteins. In a recently published study, patients with primary liver cancer were treated either with the chemotherapeutic drug 5-FU or with a combination of 5-FU and 40 mg per day of pravastatin. Median survival was 26 months in the combination therapy group, versus 10 months in the monotherapy (5-FU) group.
The highest incidences of RAS mutations are found in adenocarcinomas of the pancreas (90%), the colon (50%), and the lung; in thyroid tumors (50%); in liver tumors (30%); and in myeloid leukemia (30%). If you have one of these cancers, you should consider requesting an immunohistochemistry for the mutated RAS oncogene or a biopsied specimen in order to ascertain whether the combination of chemotherapy and a statin drug may be effective.
Cancer patients whose tumor cells have a mutant p53 oncogene are far more likely to benefit from soy extract supplementation. Only a pathology examination of the actual cancer cells can determine p53 status. An immuno-histochemistry test can help to determine the p53 status of tumor cells. The following laboratory can perform this new test:
1010 Third Avenue, Suite 203
New York, N.Y. 10021
IMPATH Laboratories measures mutant p53. If the test is positive, you have mutant p53 and are more likely to benefit from soy extracts. If the test is negative, it indicates that you have functional p53 and are less likely to benefit from soy extracts. The Foundation realizes that many cancer patients seeking to use soy supplements may find it difficult to have an immunohistochemistry test performed to ascertain p53 status. In order to find out whether you have p53, please contact your oncologist and ask him to request this test from IMPATH. IMPATH is unable to provide information about the likelihood of p53 expression on an individual basis without samples and test requests from your treating oncologist.
Another of the most widely studied molecular changes in epithelial malignancies is mutation in the p53 tumor suppressor gene. A p53 mutation has been found in approximately 50% of solid tumors.
The p53 gene product is regarded as a cell-cycle checkpoint, arresting progression through the G phase of the mitotic cycle in response to cellular injury and allowing time for repair of replication errors. Mutant p53 allows tumor cells to bypass the cell cycle constraints that facilitate repair or promote apoptosis (programmed cell death).
In addition, p53 dysfunction promotes the spontaneous emergence of mutant cells and encourages the progression of cancer. Mutant p53 might restrict therapeutic efficacy, since many cancer drugs and radiotherapy operate via the induction of DNA damage and p53-dependent apoptosis. Clinically, the presence of p53 mutations is indeed associated with intransigence to treatment, and both in vitro and in vivo studies with human cell lines and transplantable tumors have demonstrated enhanced survival of p53 mutant or null cells in the face of normally lethal concentrations of cytotoxic drugs and ionizing radiation. A determination of p53 status by immunohistochemistry can help to ascertain whether genotoxic chemotherapy and/or radiotherapy are likely to work, and can even help determine whether natural therapies such as soy genistein will be effective.
In a recently published study, genistein was shown to inhibit growth and induce differentiation in human melanoma cells in vitro. The effects of genistein were regulated by cellular p53. Functional p53-containing cells were not suppressed by genistein. However, mutant p53-containing cells were significantly more sensitive to genistein's inhibitory and cell-differentiating effects.
IMPATH Laboratories, cited earlier in this protocol, can ascertain immunohistochemistries, which will determine RAS and p53 status.
In patients affected with different tumors, blood clotting disorders are frequently observed. The biological processes leading to coagulation are probably involved in the mechanisms of metastasis. About 50% of all cancer patients, and up to 95% of those with metastatic disease, show some abnormalities, a prethrombic state, in the coagulation-fibrinolytic system. Thromboembolic complications are seen in up to 11% of cancer patients, and hemorrhage occurs in about 10%. Thromboembolism and hemorrhage, taken as a whole, are the second most common cause of death after infection.
In a recently published study, subclinical changes in the coagulation-fibrinolytic system were frequently detected in lung cancer patients. Five conventional tests and one new test of blood coagulation-that is, platelet count (P), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (F), and D-Dimer of fibrin (DD)-were prospectively recorded in a series of 286 patients with new primary lung cancer. A prethrombotic state (depicted by a prolongation of PT, PTT, and increase of D-Dimer of fibrin) was significantly associated with an adverse outcome.
Anticoagulant treatment of cancer patients, particularly those with lung cancer, has been reported to improve survival. These interesting, though preliminary, results of controlled trials lend some support to the argument that activation of blood coagulation plays a role in the natural history of tumor growth. Two recent studies compared the effectiveness of standard heparin with low molecular weight heparin (LMWH) in the treatment of deep vein thrombosis (DVT). In both studies, mortality rates were lower in the patients randomized to LMWH. The analysis of these deaths reveals a striking difference in cancer-related mortality.
Cancer-related mortality of patients treated with standard heparin was 31%, versus only 11% among those treated with low molecular weight heparin. This difference cannot be attributed solely to thrombotic or bleeding events. Because large numbers of cancer patients were included in the studies, it seems unlikely that patients with more advanced tumors were present in the standard heparin group. Although it is also possible that standard heparin increases cancer mortality, such an adverse effect has not been reported. These considerations suggest that low molecular weight heparin might exert an inhibitory effect on tumor growth that is not apparent with standard heparin. The evidence of lowered cancer mortality in patients on LMWH has occasioned renewed interest in these agents as antineoplastic drugs. If your oncologist will not test for thrombotic risk factors, contact the Life Extension Foundation at 1-800-544-4440 .
In order to assess the effectiveness of immune-boosting therapies, a complete immune cell subset test could be performed bimonthly in order to measure CD4 (T-helper) total count, CD4/CD8 (T-helper to T-suppressor) ratio, and NK (natural killer) cell activity.
CD4 T-cells have been shown to differentiate into TH1 or TH2 cells, with different cytokine profiles and functions. TH1 cells produce interleukin-2 and gamma interferon, activate macrophages, and cause delayed hypersensitivity reactions, whereas TH2 cells produce interluken-4, interleukin-5, and interleukin-10, cause eosinophilia, and are more specialized in providing B cell (antibody) help for immunoglobulin production. The differential development of these immune system subjects is a major determinant of the outcome of physiological as well as pathological immune responses to cancer.
One of the soluble factors secreted by monocytes, interleukin-12, is a major cause of differentiation of T-cells toward the TH1 type, while suppressing TH2 cytokine development. The capacity of interleukin-12 to stimulate growth and gamma interferon production in T-cells and NK cells is probably the main reason for its TH1-inducing capacity.
Another product of activated monocytes, prostaglandin E2, has been shown to be an important regulatory factor in inducing TH2 responses. PGE2 affects T-helper responses opposite to interleukin-12: the synthesis of TH1 cytokines (interleukin-2 and gamma interferon) is much more sensitive to inhibition by PGE2 than is TH2 cytokine production (IL-4, IL-5, IL-10). Because TH1 and TH2 cytokines negatively cross-regulate each other's production, the selective inhibition of TH1 cytokines by PGE2 could result in dominant TH2 responses. These findings provide opportunities to treat patients with dominant TH2 responses by selectively inhibiting synthesis of PGE2 during therapy, as this would increase interleukin-12 production and cause a shift toward TH1 cytokine production.
Many human tumors-including gastric, colon, estrogen-receptor-negative breast, prostate, and lung tumors-produce more prostaglandin E2 than their associated normal tissues. The mechanisms and implications are not fully understood, but PGE2 may act as a tumor promoter in tumor angiogenesis, in cachexia (wasting syndrome), and in the suppression of immune function.
Prostaglandins are synthesized from arachidonic acid by the enzyme cyclooxygenase. There are two isoforms of cyclooxygenases: COX-1 is expressed constitutively in most tissues and helps maintain gastric mucosal integrity; COX-2 is inducible and is associated with cellular growth and differentiation. In a recently published study, PGE2 was shown, for the first time, to upregulate the MRNA levels of its own synthesizing enzyme, COX-2, in four lines of human cells. In this regard, it is conceivable that cells continuously sustain their growth, in part, by using extracellular PGE2 that they themselves produce and release to up regulate the expressions of COX-2 (and possibly other growth-related genes). Elevated COX-2 expression may make cancer cells resistant to apoptosis. Inhibition of excess activity with COX-2 specific nonsteroidal anti-inflammatory drugs might restore the cell's ability to die by apoptosis and so cause tumor regression.
Super aspirins that selectively inhibit COX-2 are being developed by several drug companies for the purpose of avoiding the side effects of NSAIDS. The currently commercially available NSAIDS are non-selective COX inhibitors and are associated with peptic ulceration in the stomach. Nimesulide is a novel NSAID that is 100 times more selective for COX-2 than for COX-1. In a recently published study, patients received either nimesulide or aspirin for 14 days. PGE2 formation fell markedly in the nimesulide treated patients, whereas aspirin had no effect. In contrast, nimesulide had no significant effect on thromboxane B2, which was suppressed by aspirin. Nimesulide suppressed COX-2 in vivo with no detectable effect on platelet COX-1.
Nimesulide has been commercially available throughout most of the rest of the world for more than 10 years. It has not been licensed by the FDA for use in the United States. The Life Extension Foundation has identified sources that will ship nimesulide to Americans for personal use. There are also COX-2 inhibiting drugs approved by the FDA, such as Lodine XL, Celebrex, and Vioxx.
Lodine is an FDA-approved arthritis drug that interferes with COX-2's metabolic processes. The maximum dosage for Lodine is 1000 mg daily. Everyone now appears to be using Lodine XL extended-release tablets for convenient once-a-day dosing. The Lodine XL 500-mg tablet enables physicians to prescribe the maximum dosage of Lodine XL-1000 mg per day-as 2 tablets in a single daily dose. As with any NSAID, extreme caution and physician supervision is a must. The most common complaints associated with Lodine XL use relate to the gastrointestinal tract. Serious GI toxicity such as perforation, ulceration, and bleeding can occur in patients treated long term with NSAID therapy. Serious renal and hepatic reactions have been reported rarely. Lodine XL should not be given to patients who have previously shown hypersensitivity to it or in whom aspirin or other NSAIDs induce asthma, rhinitis, urticaria, or other allergic reactions. Fatal asthmatic reactions have been reported in such patients receiving NSAIDs.
Nimesulide is a safer COX-2 inhibitor but is not approved by the FDA. It is available from Mexican pharmacies or can be ordered by mail from European pharmacies. The suggested dose for nimesulide is two 100-mg tablets a day. It is important that your physician know you are taking nimesulide as an adjuvant cancer therapy.
Cancer has long baffled medical science. The debilitating, frequently fatal disease often spreads throughout the body at an alarming rate. Until recently, scientists did not fully understand why. Dr. Judah Folkman, a professor of surgery at Children's Hospital in Boston, an affiliate of Harvard Medical School, has spent the last 30 years championing a controversial theory.
Almost every tissue in the body derives blood from the thinner-than-hair capillaries that lace our tissues. Through capillaries, nutrients, oxygen, and various signaling molecules diffuse into cells. Tumors start out without circulation. In early stages, they are limited to a trickle of nutrients that can diffuse from the nearest capillary. Then, somehow, tumors begin to stimulate healthy tissue to make thousands of new blood vessels to supply the cancerous growth. Without this ability to nourish itself and grow, a tumor cannot enlarge.
At the same time, a primary tumor also sends chemical signals that prevent other tumors from growing in other parts of the body. When the tumor is removed, there is nothing to stop other tumors from growing elsewhere. That's why some people become riddled with cancer after undergoing tumor removal.
In recent years, several drugs-including interferons, steroids, and certain hormonal agents-have been developed to stop or slow angiogenesis. In fact, at least 11 anti-angiogenic drugs are in clinical trials now, and three have proved effective enough to make it to the final phase. Some of the drugs, such as endostatin, are derived from proteins; others are based on smaller molecules. Ironically, one promising drug now on trial is thalidomide, which at one time was sold as a sedative, causing notorious birth defects in the children of women who took it.
Another drug, 2-methoxyestradiol (2-ME), is a natural estrogen metabolite believed to be an inhibitor of angiogenesis and also an antitumor agent. Dr. Robert D. Amato and colleagues at Children's Hospital discovered in preclinical studies that 2-ME inhibited the growth of breast cancer cells and stopped tumors from sprouting new blood vessels.
In March of 1999, researchers reported that 2-methoxyestradiol (2-ME) inhibited growth and tumorigenesis in human pancreatic cancer cells. They reported that 2-ME inhibited the growth of these cell lines 50 to 90% (Clin. Cancer Res., 1999 March; 5:493-99).
In addition, the NCI is investigating a drug called Col-3 and negotiating with several biotechnology companies to examine other anticancer compounds. But of all the anti-angiogenic drugs, endostatin and angiostatin appear to hold the greatest potential for saving lives.
Angiostatin and endostatin drugs were discovered by Dr. Michael O'Reilly, a research fellow at Children's Hospital who has worked closely with Folkman. (O'Reilly discovered angiostatin first.) The cancer-preventing chemical turned up in the urine of mice afflicted by large tumors. Angiostatin, O'Reilly later determined, is used by the human body as part of a blood-clotting mechanism.
Endostatin appears to be produced by tumors to stop other tumors from developing throughout the body. O'Reilly and Folkman found that the drugs could eradicate several forms of cancer in mice by starving tumors of nutrient-rich blood. In fact, the drugs were so powerful that they shriveled tumors in mice that would have weighed several pounds in a human being. Unlike some anticancer drugs, though, endostatin and angiostatin do not harm normal cells. In addition, the new drugs suppress metastasis, the process by which tumor cells spread to other sites in the body.
Folkman called the protein combination "very promising" when he announced the discovered in May of 1998, but added, "We have to be careful with expectations. You always have the risk that something will fail. But if [the drugs] work in patients as well as they work in laboratories-and that's a big if-then one might hope that they improve our ability to treat cancer."
Scientists are excited about the new drugs because cancer is a difficult disease to treat with existing medicines. Tumor cells can do things with their genes that are amazing. They can shuffle their genetic information. They can amplify certain genes. They can turn off some genes and mutate others. Because you're dealing with a moving target, cancer can be hard to hit with a killing drug.
In addition, conventional cancer therapies often cause severe side effects. That's because the drugs slow down cell division, particularly in the gut and bone marrow, where cells divide rapidly. Angiostatin and endostatin, however, slow cell growth only in blood vessels and in the heart, where cells divide much less frequently. Thus, although the new drugs don't appear to cause side effects such as the nausea often produced by chemotherapy, they could cause bleeding and difficulty with wound healing, two potential problems that doctors will be monitoring closely.
Another problem with existing cancer drugs is that they sometimes stop working after patients develop a resistance to them. Of the more than 500,000 annual deaths from cancer in the United States, many follow the development of resistance to chemotherapy.
Drugs that work at first often lose effectiveness over time because cancer cells divide rapidly and sloppily, forming thousands of mutant cells. If any of these mutant cells resists the anticancer drugs, it divides and forms a drug-resistant line of cancer cells. That's what happened after scientists gave a conventional anticancer drug to mice with aggressive lung cancer. The drug controlled the tumors for 13 days, but the cancer in the mice soon developed a resistance to the drug, and the tumors resumed growing.
To find out whether tumors would develop resistance to angiostatin and endostatin, researchers gave the new drugs to mice in an on-off cycle. In other words, they attempted to stimulate any drug resistance the mice might develop for the new medicines. Remarkably, there was no resistance, no matter how many times the scientists gave the drugs to the mice. Every time the mice received the blood-vessel inhibitors, their tumors shrank as rapidly as they had the first time they were exposed to the drugs.
What accounts for the lack of resistance to the new drugs? Angiogenesis occurs when genetically stable endothelial cells in blood vessels divide to build new blood vessels. It is those cells that the inhibitor drugs affect.
The tumor cells could mutate and develop resistance, but it will be more difficult for the endothelial cells to do so, explains James Mixson, a research assistant professor at the University of Maryland School of Medicine who also studies angiogenesis in mice. "Endostatin and angiostatin are not directed at the actual tumor cell, but rather at the blood vessels that feed it," says Dr. John W. Holaday, chairman, president, and chief executive officer of EntreMed, a small biotech company in Rockville, MD, that produces endostatin. Thus, Holaday says, the drugs retain their tumor-shrinking abilities.
Even more important is the fact that the new drugs appear to keep on working even after therapy is discontinued. After mice stopped taking the drugs, for example, tumors remained dormant for up to 165 days. That's the human equivalent of 16 years. All endostatin-treated mice remained healthy and gained weight normally, according to studies completed thus far.
How is it that tumors remain dormant after the drug therapy is stopped? Perhaps, researchers speculate, the drugs leave a residual "capsule" of angiogenesis inhibitors around the tumor. Or they may initiate a sort of programmed cell death in tumors.
Tests in Mice
In trials with mice, endostatin and angiostatin worked remarkably well to kill cancers in the colon, prostate, breast, and brain. Twenty mice had large cancerous growths, which researchers removed. Ten mice were given salt water and ten were given angiostatin. There was no recurrence of cancer in any of the ten mice treated with angiostatin, but all of the water-treated mice developed new cancers.
Endostatin was given to mice in cycles. Small amounts of the protein caused tumors to shrink until they were barely visible. Treatment then was stopped and did not begin again until tumors had grown to more than 1% of body size in the mice. Miraculously, endostatin not only shrank the tumors, but caused them to become dormant so that they remained inactive even after the treatment had ended.
Initial Problems with Replication
Scientists from the NCI were unable to reproduce some initial study results involving endostatin and angiostatin. Researchers attributed the failure to technical problems, including possible trouble in transporting the fragile proteins, or improperly injecting them in the mice. There are often many problems which must be overcome in transferring a new technique from one lab to another, explained study scientists, adding that it usually takes at least 2 years for other scientists to repeat an experiment and publish results.
Eventually, other scientific teams, including one from the NCI, succeeded in independently testing endostatin and angiostatin. The two new drugs, which block the tumor blood vessels, were independently demonstrated to be incredibly effective at preventing the growth of cancers in mice, even in those with large tumors.
But several steps had to be taken before human trials could begin. First, scientists had to figure out a way to get adequate supplies of endostatin for preclinical and initial human clinical trials. So far it has been difficult to produce the large quantities needed for human tests. To overcome the problem, the NCI is working closely with EntreMed. Researchers are developing bacterial, mammalian-cell, or yeast "factories" that produce the proteins.
Scientists must also ensure that drugs produced for the trials are free of any impurities that might cause side effects in people. In recent months, researchers have developed a drug-production process that ensures purity. As part of the preclinical development process, researchers must perform necessary toxicologic and pharmacologic studies of the new drug. Scientists have been developing tests that measure the drug's action on body chemistry and organ systems. Required safety testing will follow.
Although endostatin and angiostatin have been used in combination to treat mice, the human trials will involve only endostatin. Presumably, angiostatin will be tested later in humans. During the first phase of the endostatin trials, scientists will test for adverse side effects and will also look for signs that the drug is halting the growth of tumors. If the drug is found to be safe, it will be tested for effectiveness.
The first phase will begin at Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Massachusetts General Hospital in Boston. Candidates will have tumors caused by lymphoma or cancers of the colon, breast, or other organs. Additional, similar phase I tests will begin after the Boston trials. These will be done at the University of Texas, M.D. Anderson Cancer Institute in Houston and at the University of Wisconsin's Comprehensive Cancer Center in Madison. Both sites will conduct trials on 15 to 25 patients with solid tumors caused by lung cancer, lymphoma, breast cancer, colon cancer, and prostate cancer.
NCI investigators hope that the new drugs will work in humans as well as it has worked in mice, but there are several variables to consider. So far, scientists have been treating tumors that were transplanted in mice. The biology of transplanted tumors is different from that of naturally occurring tumors. Often transplanted tumors are not accurate predictors of what will happen with natural human cancers.
Laboratory animals such as mice don't metabolize drugs the same way that humans do. This can affect the success of treatments with proteins. Because humans are much larger than mice, they will require much larger quantities of the drug. Scientists don't know what effect large amounts of endostatin might have on humans. Other anti- angiogenesis drugs have shown promise in the laboratory and then performed poorly in human tests. Interleukin-2, for example, was very successful in treating tumors in mice. But subsequent studies in people showed that it caused significant side effects such as a severe drop in blood pressure and leaking of fluid from blood vessels.
What the Future Holds
Human trials of endostatin will enable researchers to learn much more than they now know about cancer and how it kills. In fact, scientists may be able to learn more about every stage of cancer development, and that knowledge could help them to devise more innovative treatments.
If the new drug works in humans, it eventually will become available for consumption by patients. Medications in late-phase clinical trials may be approved by the U.S. Food and Drug Administration for general use as cancer treatments within 2 to 5 years. Some anti-angiogenesis drugs are already at that stage. These include Marimastat, a matric metalloproteinase inhibitor, and thalidomide, a drug with multiple mechanisms that has shown some evidence of biologic activity in gliomas (brain tumors) and Kaposi's sarcoma.
If all goes well, endostatin may become available early in the next century. But some patients may be able to get it sooner. The FDA sometimes approves "compassionate use" for promising drugs that have not been fully approved. The compassionate-use mechanism allows patients to receive such drugs if no other satisfactory options exist.
But, at this point, no one knows how costly the drug might be-or whether it will have unforeseen long-term side effects. It is likely that scientists will discover that endostatin is effective against some tumors at a particular stage in the disease process. As such, the drug could be valuable in treating cancer as a chronic disease, enabling patients to live longer, healthier lives.
Treating cancer is a lifetime commitment. The good news is that scientists are developing new cancer therapies at the fastest pace in medical history. The bad news is that all this science still requires FDA approval, which means millions of cancer patients will die in the FDA's "waiting room."
Medical oncologists do not require FDA approval to prescribe drugs like COX-2 inhibitors and the "statins" to the cancer patient. Cancer patients, however, require a continuous flow of new information to make sure they are getting the best therapies science has to offer. Much of this new information can be found on the Life Extension Foundation's Web site www.lef.org
Members of the Life Extension Foundation receive a 96-page monthly magazine that carries exclusive and timely articles about potential cancer treatment breakthroughs from around the world. To inquire about joining the Life Extension Foundation, call (800) 544-4440.
Call (800) 544-4440 to order the following:
1. "Beating Cancer with Nutrition", Dr. Patrick Quillin with Noreen Quillin.
2. "An Alternative Medicine Definitive Guide to Cancer", W. John Diamond, M.D. and W. Lee Cowden, M.D. with Burton Goldberg.
3. "Cancer Therapy", The Independent Consumer's Guide to Non-toxic Treatment and Prevention, Ralph W. Moss, Ph.D. (also the author of "The Cancer Industry").
Please refer to the References section at the end of this book for additional studies.
For some forms of cancer, you may be able to get into a free program utilizing experimental cancer therapies sponsored by the National Cancer Institute. For information about experimental cancer therapies, call (800) 4-CANCER. Make sure you do not enroll in a study where you may be part of a placebo group or where the toxicity of the drug may potentially kill you before the cancer does.
LEUKEMIA and LYMPHOMAS
Please note: It is the purpose of the Foundation to provide relevant information to our members and their health care providers from our research and review of scientific and clinical studies. It is our intention to serve as a resource upon which members and their health care providers can draw beneficial and relevant information. There has been no patient-physician relationship established between any member of the Foundation and Foundation employees. None of the Foundation members are physically examined by employees of our company and the Foundation does not intend to supplant the judgment of a patient's treating physician or substitute Foundation information for a physician's diagnosis and treatment. It is further recommended that the reader of this protocol review the actual text of any cited research and exercise his or her own personal and/or medical judgment.
Respected cancer journals are publishing articles that identify safer and more effective chemotherapy drug regimens, yet only a few medical institutions in the United States are incorporating these synergistic methods into clinical practice. Cancer patients, for the most part, undergo brutal chemotherapy regimens that have long ago proven to be ineffective.
The Foundation's chemotherapy protocol provides concise information about reducing the side effects of chemotherapeutic drugs. We recommend the utilization of natural compounds and drugs to enhance the cancer cell-killing effects of chemotherapeutic drugs via an inhibition of the overexpression of certain receptor sites and growth or "signal transduction pathways." The utilization of natural compounds may thus make possible the concept of low(er) dosing (metronomic dosing) of chemotherapeutic drugs.
Much of this protocol is highly technical and requires careful reading for proper understanding. Also, physician cooperation is essential. The cancer patient is encouraged to call the Foundation if further explanation is required.
After reading this protocol, it is important that chemotherapy patients refer to the Cancer (Adjuvant) Treatment protocol for additional information about enhancing the efficacy of chemotherapy drug therapies.
According to the National Cancer Institute, normal cells grow and die in a controlled way through a process called apoptosis. Cancer cells keep dividing and forming more cells without a control mechanism. Anticancer drugs destroy cancer cells by stopping them from growing or multiplying at one or more points in their growth cycle. Chemotherapy may consist of one or several cytotoxic drugs, depending on the type of cancer being treated.
In addition to chemotherapy, other methods are sometimes used to treat cancer. For example, your doctor may recommend that you have surgery to remove a tumor or to relieve certain symptoms that may be caused by your cancer. You also may receive radiation therapy to treat your cancer or its symptoms. Sometimes your doctor may suggest a combination of chemotherapy, surgery, and/or radiation therapy.
The goal of chemotherapy is to shrink primary tumors, slow the tumor growth, and to kill cancer cells that may have spread (metastasized) to other parts of the body from the original tumor. Chemotherapy kills both cancer and healthy cells. The goal is to minimize damage to normal cells and to enhance the cytotoxic effect to cancer cells.
Conventional chemotherapy uses a "maximum tolerated dose" (MTD) of cytotoxic (chemotherapeutic) drugs, typically every 21 days, allowing a period of rest so that healthy tissue has a chance to recover. However, neurotoxicity and damage to proliferating cells in healthy tissues remain a serious concern. Rarely are cures achieved, and responses are generally short-lived, with relapses often marked by aggressive cancers that are resistant to further use of the cytotoxic drug.
The dismal failure of most chemotherapies has fueled a broad investigation for alternatives, including drugs that target not the mutated cancer cells themselves, but rather the endothelial cells that form blood vessels. The process by which new blood vessels are formed is called angiogenesis and cancer is exceptional in initiating this response from the surrounding tissue, in order to fuel its growth Hanahan et al. 2000a). Recent studies indicate a synergistic approach of lowering the dose of conventional cytotoxic agents, rescheduling their application, and combining them with agents designed to interfere with the growth pathways (signal transduction pathways) effectively inhibiting the production of blood vessels (Holland et al. 2000).
This approach, known as metronomic dosing, uses a dosing schedule as often as every day. An amount as low as 25% of the MTD in combination with various signal transduction pathway inhibitors, targets the endothelial cells making up the vessels and micro-vessels feeding the tumor. Endothelial cells die with much less chemo than conventional cancer cells, and the side effects to healthy tissue and the patient in general are dramatically reduced (Hanahan et al. 2000b). During standard chemotherapy, the typical 21-day rest period is enough to allow the endothelial cells the chance to recover. However, with tighter scheduling the more slowly proliferating endothelial cells are unable to recover. In one recent study (Klement et al. 2000), mice were given the chemotherapeutic drug, vinblastine, at doses far below the MTD. This dose had little effect on tumor growth in the mice. A second group of mice was given the drug DC101, which blocks induction of the angiogenic factor VEGF (vascular endothelial growth factor). VEGF also protects endothelial cells from apoptosis (cell death). In this group of mice, tumor growth was slowed, as with the vinblastine, but then tumor growth resumed. However, in another group of mice given a combination of the two drugs, at a low dose, full regression of the tumors was produced with no recurrence for 6 months.
Signal Transduction Pathway Inhibition
Cell signaling pathways are any group or cascade of chemical messengers that elicit a specific response from the cell or surrounding tissue. An example of such a pathway is the binding of transforming growth factor alpha (TGF alpha) to the epidermal growth factor receptor (EGFR). Such a binding is a growth pathway for non-small cell lung cancer, and many others, causing rapid cell proliferation. The overexpression of this pathway is also implicated in tumor cells that are resistant to cytotoxic drugs. However, interference with this pathway at the epidermal growth factor receptor site effectively shuts down overexpression and the subsequent cell proliferation, making the cancer much more vulnerable to chemotherapy. The latest pharmaceutical drug designed to inhibit the EGFR is the drug, Iressa by AstraZeneca. Iressa is an orally administered specific EGF receptor site inhibitor, that when combined with various cytotoxic drugs, produces a supra-additive growth inhibitory effect (Ciardiello et al. 2001).
The following natural products have been shown to be synergistic with conventional and metronomic chemotherapy, exhibiting signal transduction inhibitory effects.
A natural alternative to Iressa is soy. Genistein, an isoflavone from soy, is known to inhibit the EGF receptor via an interference with the transforming growth factor alpha (TGF alpha) pathway (Bhatia et al. 2001). Genistein is also known to block the induction of the basic fibroblast growth factor (bFGF), a potent mitogen (growth factor) and angiogenic factor in cancers such as renal cell carcinoma and malignant melanoma (Hurley et al. 1996). Further, genistein is known to block induction of the vascular endothelial growth factor (VEGF) considered essential for angiogenesis and endothelial cell survival (Mukhopadhyay et al. 1995). The blockade of the overexpression of the EGF receptor, and the inhibition of the signaling pathways, bFGF and VEGF, is a dose-dependent response, i.e., more is better, and is a powerful adjuvant to conventional or metronomic chemotherapy.
An extract of the spice turmeric, curcumin is synergistic with genistein and strongly inhibits the angiogenic growth signals from the tumor to develop a blood supply to itself. Curcumin acts via a different mechanism than genistein to inhibit the EGF receptor, but is up to 90% effective, in a dose-dependent manner. Since two thirds of all cancers overexpress this receptor and such overexpression frequently fuels the metastatic spread of the cancer throughout the body, strong control of this receptor is desirable. Curcumin has a number of other anti-angiogenic properties that are synergistic with conventional or metronomic chemotherapy. These are:
Based on the multiple favorable mechanisms listed above, higher-dose curcumin would appear to be a useful for cancer patients to take.
As far as curcumin being taken at the same time as chemotherapy drugs, there are contradictions in the scientific literature. Some studies indicate significant benefit, whereas other studies hint at reduced benefit or even potential toxicity. One study involving curcumin concomitant use with the chemotherapy drug Irinotecan indicated potential toxicity. Therefore, Life Extension recommends that curcumin not be taken in combination with this drug. Irinotecan is also known by the names Camptosar and CPT-11. Irinotecan is mostly administered for colon cancer.
Chemotherapy drugs are highly toxic in of themselves. Whether high-dose curcumin is beneficial or detrimental depends on the type and dose of the chemotherapeutic drug used, the kind of cancer cell being attacked, and the dose of the curcumin. Until more definitive information is published, we prefer to err on the side of caution and recommend that chemotherapy patients wait 4 weeks after their last dose of chemotherapy before taking high-doses of curcumin.
The primary action of green tea is through its catechin, EGCG, which blocks the induction of vascular endothelial growth factor (VEGF) considered essential in angiogenesis and endothelial cell survival (Jung et al. 2001). In vivo studies have shown the following actions on cancer cells:
Note: It may be more efficacious to take green tea in capsule form rather than a brewed beverage as a cancer adjuvant therapy.
Spes (Latin for hope) is a Chinese herbal formula that appears to be active against cancers with a p53 mutation and also down-regulates the Kirsten-RAS mutation implicated in the rapid cell proliferation of many cancers, such as colon, lung, ovarian, and pancreatic cancer. The K-RAS mutation occurs in about 50% of all colon cancers and 90% of all pancreatic cancer. Spes also mitigates cancer pain (Pfeifer et al. 2000).
Many types of cancer cells use an enzyme called cyclooygenase-2 (COX-2) which makes the prostaglandin hormone, E2. This hormone helps fuel the growth of such cancers as colon, pancreas, estrogen-negative breast, prostate, bladder, and lung to name just a few.
Drugs that inhibit the cyclooxygenase enzyme are known as COX-2 inhibitors. The two newest COX-02 inhibitors are Celebrex and Vioxx. However, a safer COX-2 inhibitor called nimesulide is sold in Canada and Europe, but is yet to be approved by the FDA. The suggested dose for nimesulide is 100 mg twice per day. It is important that your physician know if you are taking a COX-2 inhibitor. Please refer to the "molecular oncology" section of the Adjuvant Cancer Treatment protocol for a more detailed description of the connection between COX-2 and cancer.
The regulation of cancer cell growth is
often governed by a family of proteins known as RAS oncogenes. The RAS family is
responsible for modulating the regulatory signals that govern the cancer cell
cycle and proliferation. Mutations in genes encoding RAS proteins have been
intimately associated with unregulated cell proliferation, i.e., cancer.
There is a class of cholesterol-lowering drugs known as "statins" that have been shown to inhibit the activity of RAS oncogenes. Some of these cholesterol-lowering drugs are lovastatin, simvatatin, and pravastatin.
The recommendation for dosing of lovastatin (Mevacor) is 80 mg per day for 6 months, but especially during chemotherapy. A monthly SMAC/CBC blood test is also recommended while taking a "statin" drug to monitor liver function.
A novel approach would be to combine a "statin" (such as Mevacor) with a COX-2 inhibitor. A study by Agarwal et al. (1999) showed lovastatin augmented up to fivefold the cancer killing effect of the COX-2 inhibitor, sulindac. In this study, three different colon cancer cell lines were induced to undergo apoptosis by depriving them of COX-2. When lovastatin was added to the COX-2 inhibitor, the kill rate increased fivefold.
Physician involvement is essential to mitigate against potential side effects of these drugs. Those who are concerned about potential toxicity should take into account the fact that the types of cancers that these drugs might be effective against have extremely high mortality rates.
Nutrients and hormone therapies can be
used to mitigate the toxicity of chemotherapy. The use of chemotherapy can
cause health problems over and above those of the cancer itself such as severe
heart muscle damage, gastrointestinal damage, anemia, nausea, and lethal
suppression of immune function.
Bolstering the immune system may help alleviate or lower the severity of the complications associated with chemotherapy. If possible, these methods should be undertaken several days or even weeks before any planned chemotherapy is begun and should be continued well after the chemotherapy has completed.
Vitamins E and C and N-acetyl-cysteine (NAC) may protect against heart muscle toxicity for cancer patients undergoing high doses of chemotherapy (Venditti et al. 1998). A controlled study examined the effects of these nutrients on cardiac function on a group of chemotherapy and radiation patients. One group was given vitamins C and E supplements and NAC supplements while the other group was not supplemented. In the group not supplemented, left ventricle function was reduced in 46% of the chemotherapy patients compared to those who took the supplements. Furthermore, none of the patients from the supplement group showed a significant fall in overall ejection fraction, but 29% of the non-supplement group showed reduced ejection fraction (Wagdi et al. 1996).
Vitamin C may be used to potentiate the effects of chemotherapy. Patients report improved appetite while taking vitamin C, as well as a reduced need for pain killers.
Vitamin E has been shown to protect against cardiomyopathies induced by chemotherapy. Vitamin E has also been used in combination with vitamin A and Coenzyme Q10 to reduce the side effects of the chemotherapy drug Adriamycin. Vitamin E is also complementary to chemotherapy in that it boosts the effectiveness of the drugs. The dry powder succinate form of vitamin E appears to be most beneficial to cancer patients. The more common acetate form has proven ineffective in slowing cancer cell growth in some studies, whereas natural dry powder vitamin E succinate has shown efficacy (You et al. 2001).
Coenzyme Q10 is used with vitamin E to protect patients from chemotherapy-induced cardiomyopathies. Coenzyme Q10 is nontoxic even at high dosages and has been shown to prevent liver damage from the drugs Mitomycin C and 5-FU (5-fluorouracil). Adriamycin-induced cardiomyopathies have been prevented by concomitant supplementation with CoQ10.
Caution: Some studies indicate that Coenzyme Q10 should not be taken at the same time as chemotherapy. If the studies are correct, it would be disappointing, since CoQ10 is so effective in protecting against adriamycin-induced cardiomyopathy. Adriamycin is a chemotherapy drug sometimes used as part of a chemotherapy cocktail. Until results of more research are known, it is not possible to make a definitive recommendation whether to take CoQ10 during chemotherapy.
Theanine is a unique amino acid, naturally occurring in green tea, shown in one study to enhance adriamycin concentration in tumors by 2.7-fold and reduce tumor weight by 62% over controls, whereas adriamycin by itself did not reduce tumor weight at all. Adriamycin is an anthracycline antibiotic have a wide spectrum of anti-tumor activity (Sugiyama et al. 1998). Additionally, L-theanine was shown to reverse tumor resistance to chemotherapeutic drugs through its efficacy (reduction of resistance) on the transport system of the drug into the tumor cells (Sadzuka et al. 2000).
Selenium has been used in combination with vitamin A and vitamin E to reduce the toxicity of chemotherapy drugs, particularly Adriamycin. The synergistic effect of vitamin E and selenium together to enhance the immune system is greater than either alone.
Glutathione balance is very important for the cancer patient. Glutathione is an antioxidant that protects cells from toxic compounds. Unfortunately, it is believed that glutathione actually benefits cancer cells at the expense of normal adjacent cells. A group of researchers showed that "tumor cell glutathione concentration may be among the determinants of the cytotoxicity of many chemotherapeutic agents and of radiation, and an increase in glutathione concentration in cancer cells appears to be at least one of the mechanisms of acquired drug resistance to chemotherapy."
Whey proteins used in combination with glutathione appear to reduce the concentrations of glutathione in cancer cells, thereby making them more vulnerable to chemotherapy while maintaining or even increasing glutathione levels in normal healthy cells. Researchers found that cancer cells had reduced glutathione levels in the presence of whey protein while at the same time normal cells had increased levels of glutathione levels with increased cellular growth of healthy cells. The study concluded, "Selective depletion of tumor cell glutathione may, in fact, render cancer cells more vulnerable to the action of chemotherapy and eventually protect normal tissue against the deleterious effects of chemotherapy."
Glutathione production in cancer and healthy cells is negatively inhibited by its own synthesis. Since glutathione levels are higher in cancer cells, it is believed that cancer cells would reach a level of negative-feedback inhibition for glutathione production more easily than normal cells. Chemotherapy patients should consider taking 30 to 60 grams a day of whey protein concentrate 10 days before initiation of chemotherapy, during the chemotherapy, and at least 10 days after the chemotherapy session is completed.
Note: If blood testing shows that chemotherapy has suppressed the immune system, patients should insist that their oncologists use the appropriate immune restoration drug(s), as outlined in the Cancer (Adjuvant) Treatment protocol.
Research using whey protein concentrate has led researchers to a discovery regarding the relationship between cancerous cells, glutathione, and whey protein concentrate. As mentioned above, it was found that whey protein concentrate selectively depletes cancer cells of their glutathione, making them more susceptible to cancer treatments such as radiation and chemotherapy.
This difference in glutathione status between normal cells and cancer cells is believed to be an important factor in the resistance of cancer cells to chemotherapy.
Fish oil may enhance the effectiveness of cancer chemotherapy drugs. A study compared different fatty acids on colon cancer cells to see if they could enhance Mitomycin C, a chemotherapy drug. Eicosapentaenoic acid (EPA) concentrated from fish oil was shown to sensitize colon cancer cells to Mitomycin C (Tsai et al. 1997). It should be noted that fish oil also suppresses the formation of prostaglandin E2, which is involved in the synthesis of COX-2. Colon cancer cells use COX-2 to stimulate propagation.
Nausea is one of the most common and difficult aspects of chemotherapy for cancer patients. Nausea can have secondary effects on cancer patients by interfering with their eating habits during and immediately after chemotherapy.
Drugs to mitigate chemotherapy-induced nausea include Megace and Zofran. The high cost of Zofran has kept many cancer patients not covered by insurance from obtaining this potentially beneficial drug. If you are receiving chemotherapy and experience nausea, you should be able to demand that any HMO, PPO, or insurance carrier pay for this drug. Zofran can enable a cancer patient to tolerate chemotherapy long enough for it to be possibly effective.
Medical marijuana was approved by referendum in California and Arizona, primarily for the beneficial medical use by cancer patients to alleviate nausea following chemotherapy. It is interesting to observe the objections of the federal government regarding the concept of medical marijuana as their "war on drugs" is brought to bear on an herb. Life Extension Foundation has provided financial help for the legal battle on behalf of the medical rights of those cancer patients in California and Arizona.
Researchers have embarked on evaluating the medical benefits of marijuana, and we will follow these studies and report the results to you. One study evaluated glutathione and vitamins C and E for their anti-nauseate properties. Cisplatin-induced vomiting in dogs was significantly reduced by glutathione and vitamins C and E. The anti-nauseate activity of antioxidants was attributed to their ability to react with free radicals generated by cisplatin. Ginger extract has also been shown effective in reducing nausea symptoms.
Melatonin has been shown to protect against chemotherapy-induced immune depression. One study specifically suggested that cancer patients treated with Adriamycin, a toxic chemotherapy drug, should supplement with vitamins A and E and selenium to reduce its side effects (Faure et al. 1996; Vanella et al. 1997; Korac et al. 2001).
Melatonin mediates the toxicity of chemotherapy and inhibits free-radical production. In a randomized study to evaluate the effect of melatonin on the toxicity of chemotherapy drugs, the patients receiving melatonin with chemotherapy had lower incidences of neuropathies, thrombocytopenia, stomatitis, alopecia, malaise, and vomiting.
The study suggests that adding melatonin to a chemotherapy regimen may prevent some toxic effects of the chemotherapy drugs, especially myelosuppression and neuropathies.
A study was performed to evaluate the influence of melatonin on chemotherapy toxicity. Patients randomly received chemotherapy alone or chemotherapy plus melatonin (20 mg each evening). Thrombocytopenia, a decrease in the number of blood platelets, was significantly less frequent in patients treated with melatonin. Malaise and lack of strength also were significantly less frequent in patients receiving melatonin.
Finally, stomatitis (inflammation of the mouth area) and neuropathy were less frequent in the melatonin group. Alopecia and vomiting were not influenced. This pilot study seems to suggest that administration of melatonin during chemotherapy may prevent some chemotherapy-induced side effects, particularly myelosuppression and neuropathy (Lissoni et al. 1997).
Expensive drugs like Neupogen (granulocyte colony-stimulating factor: GC-SF), granulocyte macrophage colony- (white blood cells) stimulating factor (GM-CSF), and interferon-alpha (an immune modulating cytokine) can restore immune function debilitated by toxic cancer-chemotherapy drugs. If you are on chemotherapy and your blood tests show immune suppression, you should request the appropriate immune restoration drug(s) from your medical oncologist.
Studies have shown that melatonin specifically exerts colony-stimulating activity and rescues bone marrow cells from apoptosis (programmed cell death) induced by cancer chemotherapy compounds. Melatonin has been reported to "rescue" bone marrow cells from cancer chemotherapy-induced death. The number of granulocyte macrophage colony-forming units has been shown to be higher in the presence of melatonin.
Melatonin has been seen to enhance the anti-cancer action of interleukin-2 (IL-2) and to reduce IL-2 toxicity. Melatonin use in association with IL-2 cancer immunotherapy has been shown to have the following actions:
Amplification of IL-2 biological activity by enhancing lymphocyte response and by antagonizing macrophage-mediated suppressive events.
Inhibition of production of tumor growth factors which stimulate cancer cell proliferation by counteracting lymphocyte-mediated tumor cell destruction.
Maintenance of a circadian rhythm of melatonin which is often altered in human neoplasms and influenced by cytokine exogenous injection.
The subcutaneous administration of 3 million IU a day of interleukin-2 (IL-2) and high doses of melatonin (40 mg each evening orally) has appeared to be effective in tumors resistant either to IL-2 alone or to chemotherapy (Lissoni et al. 1994). The dose of 3 million IU a day of interleukin-2 is a low dose. Serious toxicity normally begins at 15 million IU a day. At present, 230 patients with advanced solid tumors and a life expectancy less than 6 months have been treated with this melatonin/IL-2 combination. Objective tumor regressions were experienced in 44 patients (18%), mainly in patients with lung cancer, hepatocarcinoma, cancer of the pancreas, gastric cancer, and colon cancer. A survival longer than 1 year was achieved in 41% of the patients. The preliminary data show that melatonin synergizes with tumor necrosis factor (TNF) and alpha-interferon by reducing their toxicity.
The Life Extension Foundation introduced the world to melatonin in 1992, and it was the Life Extension Foundation that issued the original warnings about who should not take melatonin. These warnings were based on preliminary findings, and in two instances the Foundation was overly cautious.
First, we suggested that prostate cancer patients might want to avoid high doses of melatonin. However, subsequent studies indicated that prostate cancer patients could benefit from moderate doses of melatonin, although the Foundation still advises prostate cancer patients to have their blood tested for prolactin. Melatonin could possibly elevate prolactin secretion, and if this were to happen in a prostate-cancer patient, the drug Dostinex (0.5 mg/twice a week) could be used to suppress prolactin so that the melatonin could continue to be taken (in moderate doses of 1 to 6 mg each night).
Some doctors initially thought that melatonin should not be taken by ovarian cancer patients, but a study by Lissoni et al. (1996) indicates that high doses of melatonin may be beneficial in treating ovarian cancer. In this study, 40 mg of melatonin were given nightly, along with low doses of interleukin-2, to 12 advanced ovarian cancer patients who had failed chemotherapy. While no complete response was seen, a partial response was achieved in 16% of patients, and a stable disease was obtained in 41% of the cases. This preliminary study suggests that melatonin is not contraindicated in advanced ovarian cancer patients. It is still not known what the effects of melatonin are in leukemia, so leukemia patients should use melatonin with caution.
Cancer patients using cytotoxic chemotherapy drugs should ask their oncologist to place them on FDA-approved immune-protective drugs 1 week before the first chemotherapy drug is administered. Depending on the type of cancer and the chemotherapy regimen that will be used, two of the most important FDA-approved drugs to consider are Neupogen, a granulocyte-colony stimulating factor drug (G-CSF), or Leukine, a granulocyte-macrophage-colony stimulating factor (GM-CSF).
Neupogen or Leukine stimulates the production of T-lymphocytes, macrophages, and other immune cells that are valuable in preventing the toxic effects on the bone marrow during chemotherapy. These immune-protecting drugs enable chemotherapy to be given at a higher dose that may make it effective. Stimulated macrophages are powerful tumor killers, as has been demonstrated by clinical studies using interleukin-2 and GM-CSF, or G-CSF. In addition, colony growth factors are able to accelerate regeneration of blood cells following chemotherapy. Initial clinical experience with GM-CSF and G-CSF has shown that severe neutropenia (immune impairment) due to chemotherapy drugs may be prevented or at least decelerated, thus reducing the number of severe infections.
Alpha-interferon and/or interleukin-2 are immune cytokines (regulators) that should also be considered by cancer patients. Interferon directly inhibits cancer cell proliferation and has already been used in the therapy of hairy cell leukemia, Kaposi's sarcoma, and malignant melanoma. Interleukin-2 allows for an increase in the cytotoxic activity of natural killer (NK) cells. An oncologist must be carefully administer these drugs because the drugs can produce temporary side effects.
Retinoic acid (vitamin A) analog drugs enhance the efficacy of some chemotherapy regimens and reduce the risk of secondary cancers. Ask your oncologist to consider prescribing vitamin A analog drugs such as Accutane. Again, the use and dosage of potentially toxic drugs such as Accutane must be carefully prescribed by your attending oncologist.
Some cancer patients produce too many T-suppressor cells that shut down optimal immune function. The administration of drugs such as cimetidine helps to prevent cancer cells from prematurely shutting down the immune system. An immune cell subset blood test will reveal the status of your T-helper cells, T-suppressor cells, and NK cell count and activity. A suggested cimetidine dosing regimen for immune enhancement is 200 mg three times a day and then 400 mg taken at bedtime.
The proper administration of Neupogen or Leukine prior to the initiation of chemotherapy can dramatically reduce the immune damage that chemotherapy inflicts on the body and increase the cancer cell-killing efficacy of conventional chemotherapy drugs. Please remember that so far we have only talked about drugs that require physician administration. There are safe nutrients that can be self-administered that also protect against chemotherapy toxicity and immune impairment.
To treat low white blood cell counts, the FDA-approved drug Neupogen or Leukine may be considered by your immunologist or hematologist. Drugs such as Neupogen, Leukine, and Intron A alpha-interferon (an immune-modulating cytokine) can restore immune function debilitated by toxic cancer chemotherapy drugs. In one study, patients with refractory (resistant to treatment) solid tumors treated with standard chemotherapy and GM-CSF had a 33.3% objective response rate, versus 15% with chemotherapy alone. If you are on chemotherapy and your blood tests show immune suppression, you should demand that your oncologist use the appropriate immune restoration drug(s).
Additional Information on Cancer Treatment
Cancer patients may want to refer to the other protocols from this text.
General information sources. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health National Cancer Institute, Bethesda, Maryland 20892, and NIH Publication No. 94-1136
Soy, ten 700-mg capsules with each meal and ten at bedtime.
Curcumin, 900 mg with 5 mg piperine (an alkaloid from Piper nigrum), three capsules, four times a day on an empty stomach. Caution: Use caution when combining curcumin with other chemotherapy drugs. Do not take with the chemotherapy drug irinotecan, Camptosar, or CPT-11.
Spes, if under 150 lb: 300-mg, two capsules 2 hours before breakfast, two capsules 2 hours before dinner on an empty stomach; if over 150 lbs: take three capsules on the same schedule.
Green tea extract, five 350-capsules with each meal (three
meals per day).
L-Theanine, 500 mg disolved in water or juice, twice per day.
The following natural supplements may reduce side effects and damage caused by chemotherapy:
Vitamin E, 800 IU a day of vitamin E succinate (dry powder natural vitamin E).
Vitamin C, 4000 to 12,000 mg throughout the day.
Coenzyme Q10, 200 to 300 mg daily in a softgel oil capsule for maximum absorption. (Refer to cautions about CoQ10 and chemotherapy.)
Fish oil, 8 to 12 Mega EPA caps throughout the day. This should be balanced with at least one capsule a day of MEGA GLA (gamma-linolenic acid)
Melatonin, 3 to 20 mg at bedtime. Dose may be reduced after chemotherapy ends if too much morning drowsiness occurs. After several months, most cancer patients take 3 to 10 mg of melatonin at bedtime.
Selenium, 200 to 600 mcg daily.
Whey protein concentrate-isolate, 30 to 60 grams daily. Note: Cancer patients undergoing chemotherapy should consider taking whey protein concentrate at least 10 days before beginning therapy and during therapy and then continuing with the whey protein for at least 30 days after completion of the therapy.
Digestive enzyme capsules may reduce the gas and bloating associated with high soy intake.
Ask your oncologist to consider prescribing drugs suggested in this protocol, such as Neupogen, Leukine, and alpha interferon.
Surgery poses many risks to a cancer patient. The known side effects associated with the surgical removal of tumors include anesthesia complications, infections, and immune suppression.
A newly discovered surgery side effect of concern to cancer patients is that the removal of the primary tumor may directly stimulate the propagation of metastatic lesions. The theory is that an intact primary tumor regulates the growth of metastatic lesions by naturally secreting anti-angiogenesis agents such as endostatin and angiostatin. Metastatic tumors require the formation of new blood vessels (called angiogenesis) in order to grow. Once the primary tumor has been surgically removed, the amount of endostatin and angiostatin to control new blood vessel growth is drastically reduced, and metastasized lesions begin proliferating out of control. If the immune depression that surgery induces is factored in, the failure of surgery to meaningfully prolong the life of cancer patients becomes quite understandable. Surgery takes away growth control factors (endostatin and angiostatin) while simultaneously weakening the immune surveillance that might be keeping metastatic lesions under some degree of control.
Cancer has long baffled medical science. Until recently, scientists did not fully understand why the disease so often begins rapidly spreading throughout the body after surgery. The good news is that the drugs endostatin and angiostatin are finally entering clinical trials. If the FDA ever gets around to approving these drugs, the surgical removal of a large primary tumor might actually "cure" a lot more cancer patients. In the meantime, there are other anti-angiogenesis drugs that may help prevent the rapid growth of metastatic lesions after the primary tumor is removed.
Almost every tissue in the body derives blood from the thinner-than-a-hair capillaries that lace our tissues. Through capillaries, nutrients, oxygen and various signaling molecules diffuse into cells. These mechanisms maintain health, fight disease, and allow the body to flourish and grow.
Scientists have found that tumors start out without circulation. In the early stages of tumor development, they are limited to a trickle of nutrients that can diffuse from the nearest capillaries. Then, somehow, tumors begin to stimulate healthy tissue to make thousands of new blood vessels to supply the cancerous growth-a process called angiogenesis. Without this ability to nourish itself and grow, a tumor cannot enlarge. If the blood supply can be reduced or cut off, the tumor will shrink or die.
Scientists believe that a primary tumor sends chemicals to signal new blood vessels to grow into itself, but at the same time also sends a chemical signal that prevents other tumors from growing in other parts of the body. Advanced biomedical technology has now pinpointed those signals, and most scientists accept that the angiogenesis process (stimulation of new blood vessel growth) regulates the growth of metastatic tumors.
Once the primary tumor is removed, there is nothing to stop other tumors from growing elsewhere. That's why some cancer patients often get worse after undergoing tumor removal.
In recent years, several drugs-including interferons, steroids, and certain hormonal agents-have been developed to stop or slow angiogenesis. In fact, at least 11 anti-angiogenic drugs are now in clinical trials and three have proved effective enough to make it to final phase.
Some of the drugs, like endostatin, are derived from natural proteins, while others are based on smaller molecules. Ironically, one promising drug on trial now is thalidomide, which once was sold as a sedative which caused notorious birth defects in the children of women who took it.
Another drug, 2-methoxyestradiol (2-ME), is a natural estrogen metabolite believed to be an inhibitor of angiogenesis and also an antitumor agent.
In addition, researchers are investigating a drug called Col-3 and are negotiating with several biotechnology companies to examine other anti-cancer compounds.
Of all the anti-angiogenic drugs, endostatin and angiostatin appear to hold the greatest potential for saving lives. These drugs are nontoxic and have shown efficacy against every type of cancer they have been tested against. One study showed that these drugs suppressed metastatic tumor growth rates by 90%. Another study showed primary tumors regressing to become dormant microscopic lesions.
Based on this new information, angiostatin and endostatin may greatly increase the number of cancer patients who become disease free after surgery.
Endostatin will be entered into clinical trials before the end of 1999. It is hoped that angiostatin human trials will soon follow.
For more information about human trials of endostatin, call The University of Wisconsin Cancer Connect Line, (800) 622-8922 or (608) 262-5223. Or call the M.D. Anderson Information Line, (800) 392-1611 and select option 3. For more information on current clinical trials from PDQ, the National Cancer Institute's database, call the Cancer Information Service, (800) 4-CANCER.
Physicians may request information about trials from the PDG Search Service by calling (800) 345-3300, faxing (800) 380-1575, or e-mailing [email@example.com].
There are many anti-angiogenesis drugs in clinical studies. In some cases, the FDA may allow an unapproved drug to be released before it is officially approved. Here are some of the anti-angiogenesis drugs being tested and the sponsoring companies:
Drug Phase Sponsor
TNP-40 Phase II TAP Pharmaceuticals Inc., Deerfield, Wisc.
Squalamine Phase I Magainin Pharmaceuticals Inc., Plymouth Meeting, Pa.
Vitaxin Phase I Ixsys Inc., San Diego, Calif.
Thalidomide Phase II ExtreMed Inc., Rockville, Md.
RhuMab, VEGF Phase II Genentech Inc., South San Francisco, Calif.
SU5416 Phase II Sugen Inc., Redwood City, Calif.
Marimastat Phase III British Biotech Inc., Annapolis, Md.
Bay 12-9566 Phase III Bayer Corp., West Haven, Conn.
AG3340 Phase III Agouron Pharmaceuticals Inc., LaJolla, Calif.
Col-3 Phase I CollaGenex Pharmaceuticals, Inc.
CM101 Phase I Carbomed, Brentwood, Tenn.
A study conducted several years ago in Germany showed that, for most forms of cancer, surgical removal of the primary tumor did not result in prolonged survival compared with patients with similar cancers who refused surgery. For many forms of cancer, however, the surgical removal of the primary tumor is crucial if long-term remission is to occur. Anti-angiogenesis drugs given prior to cancer surgery may improve the chances of a long-term remission.
(For cancer patients undergoing surgery, or any other type of cancer therapy, it is important to review the new information that appears in the Cancer (Adjuvant) Treatment protocol. There are therapies discussed in the general Cancer protocol that are available now which can help protect against surgically induced immune depression, thus improving the odds of long-term survival.)
For the latest information about how cancer surgery can be made safer and more effective, continuosly check out our web-site.
For more information please visit: www.cancernet.com
Radiation therapy is given to about 60% of all cancer patients, but may inflict tremendous tissue damage to healthy cells. Radiotherapy can also cause secondary cancers after the primary cancer has been treated, leading to secondary diseases such as pneumonitis and radiation fibrosis. Radiation therapy is associated with both acute and late disease conditions that affect a patient's nutritional status.
Radiation therapy relies on the local destruction of cancer cells through ionizing radiation that disrupts cellular DNA. Radiation therapy can be externally or internally originated, high or low dose, and delivered with computer-assisted accuracy to the site of the tumor. Brachytherapy, or interstitial radiation therapy, places the source of radiation directly into the tumor as implanted "seeds."
Newer radiotherapy technologies such as stereotactic radiosurgery, which uses tightly focused x-rays or gamma rays to target tumors without widespread irradiation of surrounding tissues, may improve radiotherapy results; these approaches, however, are limited to certain types of cancers.
Radiation-induced pneumonitis can be treated with antioxidants; however, the exact cause of pneumonitis is not known. It is thought to occur as a result of excessive free radicals generated following radiotherapy.
In vitro studies have shown that large doses of radiation can cause membrane lipid peroxidation and the oxidation of protein groups. Radiation-induced pneumonitis was studied using 25 patients who underwent radiotherapy for non-small cell lung cancer (inoperable). Blood samples were taken over a 3-month period, and it was found that 40% (10 out of 25) of the patients developed pneumonitis and that these patients had significantly higher levels of free radicals and iron in their blood. Iron is a catalyst for free-radical reactions.
The risk of pneumonitis may be reduced by antioxidant therapy. There are several specific nutrients that can be taken to improve the immune system after radiotherapy. General supplementation with antioxidants such as vitamins A, C, and E, and with the sulfur amino acids cysteine and glutathione, are known to reduce free-radical damage caused by radiation therapy. For these nutrients to be effective, the nutrients or their precursors must be consumed before the radiotherapy treatment.
Radiation fibrosis is an extreme complication, without effective treatments, after radiation therapy. Surgical removal and healing of a radiation-induced fibrosis is rarely successful.
One published case involved a 58-year-old woman who developed a radiation fibrosis in the irradiated area of a squamous cell carcinoma. Following the surgery the woman was treated with a combination of pentoxifylline tablets (400 mcg 3 times daily) and vitamin E (one 400-mg capsule each day). The woman tolerated the treatment well and a noted improvement in the condition of the affected skin was seen, beginning at 4 months. A decrease in skin thickness could be demonstrated from the 6th month on, with the patient experiencing no side effects from this protocol. The data indicates a therapeutic effect on radiation-induced fibrosis by the synergistic administration of pentoxifylline and vitamin E. Pentoxifylline is a prescription drug that inhibits abnormal platelet aggregation and which may allow more blood flow to the irradiated area.
Another study published in the August 1998 issue of the British Journal of Radiology reported a "striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol." Researchers reported a 50% regression of superficial radiation-induced fibrosis regression after a 6-month administration of pentoxifylline and tocopherol (vitamin E) in half of the patients studied.
The British journal study also reported on a 67-year-old woman with a bulky radiation-induced fibrosis who, 10 years previously, had received radiochemotherapy for a small cell thyroid carcinoma with severe acute radiation side effects. She had palpable cervico-sternal fibrosis measuring 10 × 8 cm, with local inflammatory signs and functional consequences (cough, restricted cervical movement, dyspnea, and bronchitis). A CAT scan revealed deep radiation-induced fibrosis extending from the vocal cords to the carina, with laryngotracheal compression but without cancer recurrence. The patient received pentoxifylline (800 mg/day) and vitamin E (1000 IU/day), orally administered daily for 18 months. The patient exhibited clinical regression and functional improvement at 6 months and complete response with no measurable fibrosis at 18 months.
The combination of pentoxifylline and vitamin E seems to promote a significant antifibrotic effect by reversing deep radiation-induced fibrosis.
Sexual Dysfunction after Radio-therapy - New Therapy Now Available
One of the unpublicized side effects of radiotherapy is male impotency, especially in those being treated for prostrate cancer, as reflected in a study published in the July 1999 issue of the journal Urology. This study reported that a high percentage of men suffer this dysfunction after radiotherapy with little hope for recovery.
However, treatment of erectile dysfunction with the drug Viagra after radiation therapy for prostate cancer was reported a success just 1 month later (August 1999) in that same urological journal. Researchers reported the success based on research conducted by the Department of Urology at the Cleveland Clinic Foundation in Cleveland, Ohio.
The study was conducted to determine the response to Viagra in patients with erectile dysfunction after radiation therapy for localized prostate cancer. Twenty-one patients presenting with erectile dysfunction after radiation treatment for clinical T1-2 prostate cancer were studied. Two patients had undergone iodine-125 seed implantation, and the remaining 19 had undergone conformal external beam irradiation.
All 21 patients were considered to have erectile dysfunction as assessed by the International Index of Erectile Function and were prescribed sildenafil at a dosage of 50 mg, with a titration to 100 mg if needed.
Seventy-one percent of patients had a positive response, with a corresponding spousal satisfaction rate of 71%. No patient discontinued the drug because of side effects. On the global efficacy question (ability to achieve firm erections), 71% of the patients responded positively.
If you are experiencing impotency you may consider consulting your physician and having him or her prescribe 50 to 100 mg of Viagra daily to correct this sometimes overlooked adverse side effect of radiotherapy. Viagra is not without side effects, but, for otherwise healthy people, it appears safe.
Radiation-induced lung injury frequently limits the total dose of thoracic radiotherapy that can be delivered to a patient undergoing radiation therapy, limiting its effectiveness.
Several small animal studies including a study reported in the October 1998 issue of the Journal of Nutrition suggest that supplemental vitamin A may reduce lung inflammation after thoracic radiation and be an important modifiable radioprotective agent in the lung (J. Nutr., 1998 Oct; 128 :1661-64).
Researchers have also reported the radioprotective effect of beta-carotene from a study conducted on over 700 children exposed to radiation by the Chernobyl nuclear accident. The results showed that natural beta-carotene protected against the susceptibility of lipids to oxidation and may act as an in vivo lipophilic antioxidant or radioprotector.
Patients undergoing radiotherapy should be taking 25,000 IU of vitamin A a day.
CAUTION: Refer to Avoiding Vitamin A Toxicity protocol to avoid toxic overdose.
The amino acid taurine is severely depleted when people undergo radiation therapy. The March 1992 issue of the American Journal of Clinical Nutrition suggested a possible therapeutic effect of taurine supplementation relative to radiation therapy. Supplementation with 2000 mg a day of taurine is, therefore, recommended to people undergoing cancer radiation therapy.
The possible benefits of melatonin were reported in a preliminary study in the February 1996 issue of the journal Oncology (1996 Jan-Feb;53 :43-46) in which researchers suggested that radiotherapy plus melatonin may prolong the survival time and improve the quality of life of patients affected by glioblastoma.
More recently, an issue of Mutation Research (1999, March:10; 425 :21-27) reported that "high doses of melatonin are effective in protecting mice from lethal effects of acute whole-body irradiation."
Patients with brain glioblastoma generally experience a poor survival rate, which is typically less than 6 months. However, when 20 mg of melatonin were given to patients treated with radical or adjuvant radiotherapy, both the mean survival rates and the percentage of survivors after one year were significantly higher among patients treated with melatonin therapy compared with patients who did not receive melatonin. Researchers also reported that patients had reduced radiation and steroid-related toxicities when melatonin was consumed nightly.
Soy extracts have a strong impact on protecting both healthy and cancerous cells and are strongly recommended as an adjuvant cancer therapy. However researchers have documented that soy extracts may reduce the effectiveness of radiotherapy. Based on these preliminary results, cancer patients undergoing radiation therapy should avoid soy or genistein extracts 1 week before, during, and 1 week after radiation therapy, because soy may prevent radiation from killing cancer cells.
It has been found that cancer cells and normal cells will respond differently to nutrients and drugs that affect glutathione status. Some studies show that the concentration of glutathione in tumor cells is higher than that of the normal cells that surround them. This difference in glutathione status between normal cells and cancer cells is believed to be an important factor in cancer cells' resistance to chemotherapy. Whey protein concentrate has been shown to selectively deplete cancer cells of their glutathione, thus making them more susceptible to cancer treatments such as radiation and chemotherapy.
As the researchers put it, "Tumor cell glutathione concentration may be among the determinants of the cytotoxicity of many chemotherapeutic agents and of radiation, and an increase in glutathione concentration in cancer cells appears to be at least one of the mechanisms of acquired drug resistance to chemotherapy." They further state, "It is well-known that rapid glutathione synthesis in tumor cells is associated with high rates of cellular proliferation. Depletion of cancer cell glutathione in vivo decreases the rate of cellular proliferation and inhibits cancer growth."
It's difficult to reduce glutathione sufficiently in tumor cells without placing healthy tissue at risk and putting the cancer patient in a worse condition. What is needed is a compound that can selectively deplete the cancer cells of their glutathione, while increasing or at least maintaining the levels of glutathione in healthy cells. This is what whey protein appears to do.
Scientists have found that cancer cells subjected to whey proteins are depleted of their glutathione, and their growth is inhibited, while normal cells have an increase in glutathione and increased cellular growth. These effects were not seen with other proteins. Not surprisingly, the researchers concluded, "Selective depletion of tumor cell glutathione may in fact render cancer cells more vulnerable to the action of chemotherapy and eventually protect normal tissue against the deleterious effects of chemotherapy."
The exact mechanism by which whey protein achieves this is not fully understood, but it appears that it interferes with the normal feedback mechanism and regulation of glutathione in cancer cells. It is known that glutathione production is negatively inhibited by its own synthesis. Since baseline glutathione levels in cancer cells are higher than those of normal cells, it is probably easier to reach the level of negative-feedback inhibition in the cancer cells' glutathione levels than in the normal cells' glutathione levels.
Cancer patients undergoing radiation therapy may consider taking 30 to 60 grams a day of whey protein concentrate, starting at least 10 days before beginning therapy, during therapy, and then continuing for at least 10 days after completion of the therapy.
It is well established that solid tumors contain oxygen deficient (hypoxic) areas, and that cells in such areas will cause tumors to be resistant to ionizing radiation. Inoperable cervical cancer is normally treated with radiotherapy. Several previous in vivo and in vitro trials suggest an improvement of radiosensitivity by adding retinoids and alpha-interferon in squamous cell cervical cancer.
In an early pilot trial, 33 women with squamous cell cervical cancer were treated with 6 million units of alpha-interferon a day and 1 mg per kilogram of body weight of the retinoid drug Accutane a day for 12 days prior to radiotherapy. During radiotherapy, all dosages were reduced to prevent toxic side effects: 3 million units of alpha-nterferon 3 times a week and 0.5 mg per kilogram of body weight of Accutane daily were administered until the maximum dosage of radiation was reached. Twenty-nine patients were totally evaluated and four patients were still under treatment.
Complete response occurred in 26 patients, partial response in three patients, and almost all patients tolerated treatment well while toxicity was mild. Treatment with alpha-interferon and Accutane improved oxygenation of squamous cell cancers and may enhance the efficacy of radiotherapy.
In a 1998 study, German researchers conducted a 2-week pretreatment with retinoic acid plus interferon-alpha-2a prior to definitive radiation therapy in cervical cancer patients. Investigators reported a complete clinical remission of the local tumor in 19 of 22 patients after radiotherapy and additional retinoic acid plus interferon-alpha-2a treatment. In primarily hypoxic tumors, four out of five achieved complete remission (Strahlenther Onkol. 1998 [Nov]; 174:571-74).
A 1999 study published in the International Journal of Radiation Oncology Biological Physics (1999, Jan 15; 43:367-73) confirmed the German study regarding the oxygenation of cervical cancers during radiotherapy using radiotherapy plus cis-retinoic acid/interferon. Researchers found that in patients with well-oxygenated tumors, 87% (20 out of 23) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6 out of 6 patients whose primarily hypoxic tumors showed an increase of the median oxygen levels achieved a complete remission. In contrast, only 4 out of 7 patients with a low pretreatment and persisting low median O2 achieved a complete remission. Researchers concluded there are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median oxygen was found. An additional treatment with cis-retinoic acid and interferon further improved the oxygenation.
If you (or a member of your family) are undergoing radiotherapy, this new information should be brought to your physician's attention.
In animal studies, when ginseng was administered along with radiation therapies, a far greater percentage of the animals survived in the ginseng-supplemented group, compared with the group administered radiation without ginseng. Cancer patients should consider taking 2 to 4 capsules daily of Sports Ginseng by Nature's Herbs, which combines Korean and Siberian ginseng.
Shark liver oil containing standardized alkylglycerols can prevent immune impairment and irradiation injury to healthy tissues. Cancer patients should take six 200-mg standardized shark liver oil capsules a day for 30 days. Shark liver oil can cause an overproduction of blood platelets, so high doses of shark liver oil should not be taken for more than 30 days.
Worth mentioning are several other emerging cancer therapies including hyperthermia and microwave hyperthermia. Hyperthermia therapy has been used to fight metastatic cancer and is usually combined with immune therapy treatment. Microwave hyperthermia is generally used to treat a specific region or tumor. This therapy is generally combined with radiation therapy.
Millennium Health Care in Atlanta Georgia is considered one of the leading organizations for this emerging therapy and can be contacted at (770) 390-0012, or information on-line can be obtained at www.millennium-healthcare.com.
The following natural supplements may reduce side effects and damage caused by radiotherapy. In addition, they may aid in the selective destruction of cancer cells and protection of healthy body tissue.
1. Melatonin, 20 mg nightly. Dose may be reduced to 3 to 10 mg each night after 30 days if too much morning drowsiness occurs.
2. Taurine, 2000 mg daily for those patients undergoing radiotherapy.
3. Ginseng, two to four 200-mg standard dosage Ginseng Sport capsules daily.
4. Shark liver oil, six 200-mg standardized shark liver oil capsules a day for 30 days prior to radiation therapy.
CAUTION: Shark liver oil can cause an overproduction of blood platelets, so high doses of shark liver oil should not be taken for more than 30 days.
5. Pentoxifylline and vitamin E, three 400-mg pentoxifylline tablets daily with two 400-IU capsules of vitamin E.
6. Vitamin A, 25,000 IU a day (refer to Avoiding Vitamin A Toxicity protocol in order to avoid toxic overdose).
7. Vitamin C, 4,000 to 12,000 mg a day.
8. N-acetyl-cysteine (NAC), 600 mg, 3 times a day.
9. Whey protein concentrate-isolate, 30 to 60 grams a day at least 10 days before beginning therapy and during therapy, and then continuing with the whey protein for at least 30 days after completion of the therapy.
10. Alpha-interferon and Accutane. Consult your physician. A recent study reports on dosages of 6 million units of alpha-interferon and 1 mg per kilogram body weight of the retinoid drug Accutane daily for 12 days prior to radiation therapy. (During the radiation therapy sessions, the dosages were reduced to 3 million units of alpha-interferon 3 times a week and 0.5 mg per kilogram of body weight of Accutane until the maximum dosage of radiation was achieved).
Product availability: Vitamin A, vitamin C, vitamin D, vitamin E, selenium, shark liver oil capsules, whey protein concentrate, taurine, ginseng, and melatonin can be obtained by calling 1-800-544-4440 Or order online.
Product availability: Vitamins A, C, D, E, selenium, shark liver oil capsules, whey protein concentrate, taurine, ginseng, and melatonin can be obtained by calling 1-800-544-4440 or order on-line at www.lef.org. Or On-line at www.lef.org
VITAMIN B 12 assists in proper cell growth, including red and white cell formation, in energy metabolism, and in nerve function. B12 is found in animal foods, esp. liver and kidneys, eggs, fish, cheese and other meat. (B12 in soy foods may not be available to the body.)
Research has indicated that B12 (as methylcobalamin) can extend the lives of mice with cancer. Quillin claims that the combination of B12 and C is particularly beneficial, forming a cobalt ascorbate complex which has been shown to slow tumor growth in animal studies.
Other research has shown B12's usefulness in countering the production of homocysteine, in alleviating asthma and sulfite sensitivity, depression, diabetic neuropathy, low sperm counts, and tinnitus. It is thought to make nerve regeneration possible in high doses, augments T cell activities, and helps with sleep-wake rhythm disorders.
Dosage: Quillin recommends 1 mg (1000 mcg) per day. Murray recommends 1000 mcg per day (2000 or more for acute problems like tinnitus or neuropathies), and advocates the use of methylcobalamin rather than the commonly available cyanocobalamin. Methylcobalamin is immediately active in the body. One source of methylcobalamin is Life Extension Foundation which sells 1 mg and 5 mg strengths; 1-800-544-4440. No toxicities have been reported, and some sources say that dosages up to 60 mg have been tried without ill effects.
Research has indicated that B12 (as methylcobalamin) can extend the lives of mice with cancer. Quillin claims that the combination of B12 and C is particularly beneficial, forming a cobalt ascorbate complex which has been shown to slow tumor growth in animal studies. January 1997
The Super Hormone Promise explains and provides evidence for the anti-cancer benefits of DHEA. Dr. Regelson reports on DHEA's anti-tumor effects in animals, and discusses clinical research with DHEA in cancer patients. In relating his own use of DHEA in terminal cancer patients given up as "hopeless" by other doctors, he provides evidence for the safety of DHEA in humans.
"Over the course of 2 1/2 years, I gave 19 patients extremely high doses of DHEA-up to 40 mg per kilogram (kg) of weight daily in divided doses. Considering that the average patient weighs between 70 and 80 kg, this was an astonishingly high dose, between 2,800 and 3,200 mg daily.
"In nearly all cases, the DHEA was well tolerated, which to me further attested to the safety of this superhormone. Nearly all the patients said they felt better and reported a reduction in fatigue. What was particularly interesting was that the patients with the poorest prognosis-two patients with advanced renal cancer, a particularly lethal malignancy-seemed to fare the best. Although these terminal patients had limited life expectancy, DHEA arrested the growth of their cancers. One survived for another 2 1/2 years without regression of the tumor, but also without its further growth.
"The true leavening grace in this is that my patients were in stable condition and out of pain for most of their 'borrowed time'. Thus, although DHEA may not have 'cured' the cancer, it improved the overall physical condition of these patients and greatly ehanced the quality of life they had left."
DHEA Survey Results
Recently, the producers of the NBC Today Show contacted The Life Extension Foundation to ask us to locate members taking DHEA who might be willing to discus their use of the hormone on the show.
We phoned members in the New York City area who had purchased DHEA to see if they would be willing to go on national television. Most members we contacted were eager to go on The Today Show to talk about their results with DHEA replacement therapy.
What surprised us was the high percentage of very satisfied DHEA users. We didn't have to make very many calls before finding more than enough members to go on TV. We were so surprised by the enthusiasm of these members that we continued to make calls to get a larger sample of DHEA users.
Here is some of the testimony we elicited about DHEA in our survey:
"Incredible. We ride our
H. & ME., Fayettville, NY
"Improves energy, helps
S.D., Sayerville, NJ
"Lost weight, positive
G.S., West Hartford, CT
"Made me feel hyper"
D.C., Youngstown, NY
"Feels good, very pleased."
R K., New York, NY
"Able to focus more, with
J.A., Mahopac, NY
"Feels great, more energy, sleep better"
E.J., Brooklyn, NY
"Feels it helps energy
N.H., Stony Brook, NY
"Helped with extreme stress"
J.G., New York, NY
"Seems to encourage a
R.M.. Brewster, NY
M.W., Clark, NJ
"Feels very good"
P.B. Bronx, NY
"Helps with energy levels
J.R., Mastic Beach , NY
The only real difference between articles on melatonin that have appeared in Life Extension magazine and the article in The New England Journal of Medicine are the conclusions. The Foundation recommends supplemental melatonin for most people while the NEJM article, after laying out the many benefits of melatonin, concludes that, "uncontrolled use of melatonin to obtain any of these [beneficial] effects is not justified."
This conclusion shouldn't be surprising. Medical journals are almost always extremely conservative in their recommendations. The December 25, 1996, issue of the Journal of the American Medical Association (JAMA), for example, reported that selenium supplements reduced cancer mortality by 50 percent in humans in a long-term double-blind, controlled study. Yet the conclusion of the JAMA study was, "It is premature to change individual behavior." In other words, don't take selenium supplements yet!
A contradiction appearing in the NEJM article on melatonin was its criticism of people who ingest more than 300 to 500 mcg a night of melatonin, thus increasing their serum levels by 10 to 100 times the normal level found in a young person. Yet, throughout the article, the author states that these high doses (1 to 5 mg a night) are needed to obtain the many health benefits attributed to melatonin.
Here are verbatim excerpts from the NEJM article:
"There is evidence from experimental studies that melatonin influences the growth of spontaneous and induced tumors in animals. Pinealectomy enhances tumor growth, and the administration of melatonin reverses this effect or inhibits tumorigenesis caused by carcinogens.
"Data on the relation between melatonin and oncogenesis in humans are conflicting, but the majority of the reports point toward protective action. Low serum melatonin concentrations and low urinary excretion of melatonin metabolites have been reported in women with estrogen-receptor-positive breast cancer and men with prostatic cancer.
"The mechanism by which melatonin may inhibit tumor growth is not known. One possibility is that the hormone has antimitotic activity. Physiologic and pharmacologic concentrations of melatonin inhibit the proliferation of cultured epithelial breast cancer cell lines (particularly MCF-7) and malignant melanoma cell lines (M-6) in a dose-dependent manner. This effect may be the result of intranuclear down-regulation of gene expression or inhibition of the release and activity of stimulatory growth factors. Melatonin may also modulate the activity of various receptors in tumor cells.
"For example, it significantly decreased both estrogen-binding activity and the expression of estrogen receptors in a dose-specific and time-dependent manner in MCF-7 breast-cancer cells. Another possibility is that melatonin has immunomodulatory activity. In studies in animals, melatonin enhanced the immune response by increasing the production of cytokines derived from T-helper cells (interleukin-2 and interleukin-4), and as noted earlier, in mice melatonin protects bone marrow cells from apoptosis by enhancing the production of colony-stimulating factor by granulocytes and macrophages.
"Lastly, as a potent free radical scavenger, melatonin may provide
protection against tumor growth by shielding molecules, especially DNA, from
oxidative damage. However, the antioxidant effects of melatonin occur only at
very high concentrations.
(Editor's note: The NEJM defines high concentrations of melatonin as 1-5 mg per night.)
"The effects of melatonin have been studied in some patients with
cancer, most of whom had advanced disease. In these studies, melatonin was
generally given in large doses (20 to 40 mg per day orally) in combination with
radiotherapy or chemotherapy. In a study of 30 patients with glioblastomas, the
16 patients treated with melatonin and radiotherapy lived longer than the 14
patients treated with radiation alone. In another study by the same
investigators, the addition of melatonin to tamoxifen in the treatment of 14
women with metastatic breast cancer appeared to slow the progression of the
disease. In a study of 40 patients with advanced malignant melanoma treated
with high doses of melatonin (up to 700 mg per day), 6 had transient decreases
in the size of some tumor masses. It has been claimed that the addition of
melatonin to chemotherapy or radiotherapy attenuates the damage to blood cells
and thus makes the treatment more tolerable. All these preliminary results must
be confirmed in much larger groups followed for longer periods of time."
(Editor's note: Medical journals often use the term "chemotherapy" either for cytotoxic [cell poisoning] therapy, or for immune-enhancing therapies such as interleukin-2 or interferon that are far less toxic.)
"Both in vitro studies and in vivo studies have shown that melatonin is a potent scavenger of the highly toxic hydroxyl radical and other oxygen-centered radicals, suggesting that it has actions not mediated by receptors. In one study, melatonin seemed to be more effective than other known antioxidants (e.g., mannitol, glutathione, and vitamin E) in protecting against oxidative damage.
Therefore, melatonin may provide protection against diseases that cause degenerative or proliferative changes by shielding macromolecules, particularly DNA, from such injuries. However, these antioxidant effects require concentrations of melatonin that are much higher than peak nighttime serum concentrations. Thus, the antioxidant effects of melatonin in humans probably occur only at pharmacologic concentrations." (Editor's Note: The NEJM defines pharmacological doses of melatonin as 1-5 mg a night.)
"Melatonin may exert certain biologic effects (such as the inhibition of tumor growth and counteraction of stress-induced immunodepression) by augmenting the immune response. Studies in mice have shown that melatonin stimulates the production of interleukin-4 in bone marrow T-helper cells and of granulocyte-macrophage colony-stimulating factor in stromal cells, as well as protecting bone marrow cells from apoptosis induced by cytotoxic compounds. The purported effect of melatonin on the immune system is supported by the finding of high-affinity (Kd, 0.27 nM) melatonin receptors in human T lymphocytes (CD4 cells) but not in B lymphocytes."
". . . Ingestion of melatonin affects sleep propensity (the speed of falling asleep), as well as the duration and quality of sleep, and has hypnotic effects. In young adults, oral administration of 5 mg of melatonin caused a significant increase in sleep propensity and the duration of rapid-eye-movement (REM) sleep. In other studies, sleep propensity was increased in normal subjects given much lower doses of melatonin (0.1, 0.3, or 1 mg), either in the daytime or in the evening, and sleepiness in the morning was not increased. The time to the maximal hypnotic effect varies linearly from about three hours at noon to one hour at 9 p.m. The administration of melatonin for three weeks in the form of sustained-release tablets (1 mg or 2 mg per day) may improve the quality and duration of sleep in elderly persons with insomnia.
"These results indicate that increasing serum melatonin concentrations (to normal nighttime values or pharmacologic values) can trigger the onset of sleep, regardless of the prevailing endogenous circadian rhythm. The hypnotic effect of melatonin may thus be independent of its synchronizing influence on the circadian rhythm and may be mediated by a lowering of the core body temperature. This possibility is supported by the observations that the circadian cycle of body temperature is linked to the 24-hour cycle of subjective sleepiness and inversely related to serum melatonin concentrations and that pharmacologic doses of melatonin can induce a decrease in body temperature. However, physiologic, sleep-promoting doses of melatonin do not have any effect on body temperature. Alternatively, melatonin may modify brain levels of monoamine neurotransmitters, thereby initiating a cascade of events culminating in the activation of sleep mechanisms. . . .
"Exogenous melatonin thus appears to have some beneficial effects on the symptoms of jet lag, although the optimal dose and timing of ingestion have yet to be determined. It is also unclear whether the benefit of melatonin is derived primarily from a hypnotic effect or whether it actually promotes a resynchronization of the circadian rhythm. . . .
"Low nighttime serum melatonin concentrations have been reported in
patients with depression, and patients with seasonal affective disorder have
phase-delayed melatonin secretion."
(Editor's note: Some people who suffer from seasonal affective disorder [SAD] may want to reduce or eliminate melatonin supplementation during the dark months of the year.)
A Role in Aging
"The decrease in nighttime serum melatonin concentrations that occurs with aging, together with its multiple biologic effects, has led several investigators to suggest that melatonin has a role in aging and age-related diseases. Studies in rats and mice suggest that diminished melatonin secretion may be associated with an acceleration of the aging process. Melatonin may provide protection against aging through attenuation of the effects of cell damage induced by free radicals or through immuno-enhancement. However, the age-related reduction in nighttime melatonin secretion could well be a consequence of the aging process rather than its cause, and there are no data supporting an anti-aging effect of melatonin in humans."
"There is now evidence to support the contention that melatonin has a hypnotic effect in humans. Its peak serum concentrations coincide with sleep. Its administration in doses that raise the serum concentrations to levels that normally occur nocturnally can promote and sustain sleep. Higher doses also promote sleep, possibly by causing relative hypothermia. Exogenous melatonin can also influence circadian rhythms, thereby altering the timing of fatigue and sleep. . . .
"It is tempting to speculate that the hormone also has antigonadal or antiovulatory effects in humans, as it does in some seasonal and nonseasonal mammalian breeders, but this possibility has not been substantiated. The antiproliferative and anti-aging effect of melatonin are even more problematic. Uncontrolled use of melatonin to obtain any of these effects is not justified."
(Editor's note: Very high doses of melatonin [75 mg] are being used as a birth control pill in Europe.)
The Foundation's Conclusions
The human race is afflicted with chronic, degenerative diseases and the inexorable deterioration of aging. If published scientific studies show that a natural hormone supplement can boost immune function, scavenge free radicals, fight cancer, induce youthful sleep patterns and possibly slow aging, then we think most people should be taking this hormone.
The average reader of Life Extension magazine is "programmed" by nature to die within 35 years. Any supplement that can help prevent lethal diseases, extend average lifespan in animals and improve sleep should be recommended for widespread public use.
Both inorganic and organic forms of selenium inhibit mammary tumorigenesis and mammary cell growth, but in different ways. Organic selenium appeared to inhibit cell growth by inhibiting cell cycle regulatory proteins. Inorganic selenium produced a strong genotoxic effect on tumor cells.
Cancer Letters Vol 107, Issue 2 1996
Conventional therapy is of little value in treating glioblastoma multiforme (a type of brain cancer). Genistein is a component of soy that interferes with cancer cell proliferation by inhibiting tyrosine kinase activity. Human glioblastoma multiforme cancer cells were exposed to genistein and other potential tumor inhibitors in vitro. Brain cell infiltration was completely inhibited by genistein.
Neurosurgery Vol 40, Issue 1, 1997
Preventing Colon Cancer
Women with high folate intake are 60 percent less likely to develop adenomas of the colon than women with low folate intake. Men with high intake of vitamin E are 65 percent less likely to develop colorectal adenomas as men with low vitamin E intake. (Adenomas are considered precursors to colon cancer).
American Journal of Epidemiology, Vol 144, Issue 11, 1996
Green tea extracts inhibit free radical activity via several mechanisms. In the study, different fractions of green tea were shown to 1) protect certain brain cells from iron-induced lipid peroxidation; 2) act as iron-chelating agents; 3) scavenge the dangerous hydroxyl radical; and 4) scavenge lipid radicals (fat-based free radicals).
Biochemica et Biophysica Acta Vol 1304, Issue 3 1996
The effects of the main component of Japanese green tea (epigallocatehcin gallate) were evaluated in human acute myeloblastic leukemia cells. The green tea fraction inhibits the proliferation of the cells in all cases examined. The mechanism of action is the blockade of growth factors. Researchers conclude that ". . . this green tea fraction might be a new therapeutic tool for acute myeloblastic leukemia patients."
Life Sciences Vol 60, Issue 2, 1996
Versions of these reports were first distributed in newsletter format free to members of The Life Extension Foundation, in keeping with our commitment to keep members abreast as early as possible of research, breakthroughs and exciting new products. For information about joining the Foundation and receiving this information as soon as it is available, call 1-800-841-5433.
after intensive chemotherapy and/or radiation
Am J Clin Nutr; 55(3):708-11 1992
Taurine, a nonessential amino acid (AA), is the most abundant free AA in the intracellular space. We measured plasma AA concentrations in 36 patients 7-28 d after intensive chemotherapy and/or radiation. Plasma taurine concentrations were uniformly low in all patients (20.0 +/- 6.4 mumol/L, mean +/- SD). Plasma taurine in 11 healthy volunteer control subjects was 45.0 +/- 20.3 mumol/L (P less than 0.001). Other AA concentrations, specifically those of precursor AAs methionine and cystine, were normal. We prospectively measured plasma AA concentrations in 12 patients before starting and 6-10 d after completing intensive cytotoxic treatment. Values before treatment were 37.2 +/- 11.6, 109.6 +/- 30.7, and 18.5 +/- 4.8 for taurine, cystine, and methionine, respectively, and were 24.3 +/- 6.0, 111.2 +/- 23.8, and 24.0 +/- 14.5 after treatment. Pretreatment plasma taurine correlated directly with the magnitude of decrease in plasma taurine during cytotoxic treatment (n = 12, r = 0.85, P less than 0.01). Intensive cytotoxic chemotherapy and/or radiation leads to a reduction in plasma taurine concentrations without any change in its precursor AAs, methionine and cystine. The clinical relevance of plasma taurine depletion will need further study.
Effect of glutaurine
and its derivatives and their combinations with radiation protective substances
upon irradiated mice
Acta Radiol Oncol Radiat Phys Biol; 20(5):319-324 1981
The radiation protective effects of glutaurine (gamma-L-glutamyl-taurine, Litoralon), and of some of its derivatives, as well as of their combinations with substances of the amino-alkyl-thiol group, have been investigated in mice. The results suggest that glutaurine possesses a radiation protective effect in animals irradiated with LD50/30 of roentgen rays and 60Co gamma rays. The compound has a favorable effect also when administered after irradiation. Among the combinations best results were obtained by its simultaneous administration with subminimal doses of S-beta-aminoethyl-isothiuronium (AET) or cystamine. Some of its derivatives also exhibited considerable protection against irradiation with roentgen rays.
Effect of mixed gamma-neutron
irradiation on taurine penetration through cellular membranes of rat peripheral
Res. Inst. Biology and Biophysics, V. V. Kuibyshev Tomsk State Univ., Tomsk,
USSRCapacity of rat peripheral blood WBC for transmembrane transfer of taurine was studied in vitro in normal controls and 24 hr after mixed gamma-neutron (70%) irradiation (GNI: 350 rads). Four hr after GNI, the number of WBC decreased and equaled 31% of the initial level; the amount of taurine increased within the same period, and 24 hr after GNI it was 3x the initial level. At the same time, an increase in the protein content of WBC was seen. Irradiation was found to change the membrane permeability. It was noted that 24 hr after GNI, the system of taurine transport in the irradiated cells became more specific: the affinity to taurine increased, and the d,l-beta-alanine- dependent transfer system began to play a more important role. In another series of experiments, it was found that damage to cell membranes caused by WBC trypsinization decreased the taurine content 5x, showing that the greater part of taurine is localized inside the cells, where it apparently participates in metabolism.
Taurine and sh-group content in the
platelets of irradiated rats
The association between the content taurine and SH-groups of platelets during radiation sickness was studied in albino rats. Animals were irradiated with 650 R and sacificed 1, 4, 7, 12 and 21 days later. The levels of taurine and SH-groups in separated platelets was measured per protein unit. The development of radiation sickness resulted in a sevenfold decrease in the content of platelet taurine on days 4-7 of irradiation and twofold decrease in SH-group content on day 12 of irradiation. On day 21,the content of both taurine and SH-groups showed normalization. The decrease in taurine and SH-groups content may have been due to radiation-induced elevation of protein adsorption on platelet membrane.
Effect of alkoxyglycerols on the
frequency of injuries following radiation therapy for carcinoma of the uterine
Acta Obstet Gynecol Scand; 56(4):441-448 1977
The occurrence of complications of intracavitary and external radiotherapy of cervical carcinoma was studied in 657 patients given radium only (controls), 595 patients treated prophylactically with shark liver oil alkoxyglycerols (preparation AT-18: 0.6 g/day, po) before (for 7 days), during, and after (for 1-3 mo) radiotherapy, and 523 patients given a 'non-prophylactic' course of alkoxyglycerols during and after radiotherapy. The follow-up period was greater than 5 yr in 1,496 patients (including all controls) and 3.5 yr in 279 patients. Radiation damage to the bladder, ureters, intestine, and rectum and complex damage caused by tumor growth, with or without radiation injury, were studied. High-dose radium (intrauterine, greater than 100 mg; vaginal application, greater than 90 mg) caused an unexpectedly large number of radiation injuries, but this was greatly reduced by alkoxyglycerol therapy, especially prophylactic therapy. In all groups studied, prophylactic and non-prophylactic therapy greatly reduced radiation injuries. Only prophylactic therapy reduced complex damage (by about 60% in the high-dose radium group, about 67% in the total group). The data suggested that prophylactic alkoxyglycerol therapy could transform complex damage to a radiation injury by inhibiting the tumor-growth component of complex injuries. Since about 99% of the patients with complex injuries died within 5 yr, such prophylactic therapy could increase the 5-yr survival rate. In vivo radioprotective activity of Panax ginseng and diethyldithiocarbamate In Vivo; 7(5):467-70 1993 Studies were performed to determine whether the water fraction and the alkaloid fraction of Panax ginseng protect against radiation damage to jejunal crypts of N:GP(s) mice and induction of micronuclei (MN) in cytokinesis-blocked (CB) lymphocytes of C57BL/6 mice after in vivo irradiation with 60Co gamma-rays. The radioprotective effect of ginseng was compared with the effect of diethyldithiocarbamate (DDC). Jejunum was protected by the water fraction (2 mg/ml of drinking water) (P 0.001) and the alkaloid fraction (5.4 mg/day, P.O.) (P 0.005), both pre-and post-treatment, and by DDC (1000 mg/kg B.W., single I.P., 30 minutes before 15 Gy irradiation) (P 0.001). The frequency of radiation (3 Gy)-induced micronuclei in spleen lymphocytes was also reduced by pretreatment of water fraction, alkaloid fraction of ginseng (P 0.025) and DDC (P 0.001). The data suggested that the water fraction and alkaloid fraction of Panax ginseng may reduce cell damage caused by gamma-rays, especially damage to DNA molecules, and play a role in the repair or regeneration process of damaged cells.
mutagenesis and transformation by root extracts of panax ginseng in vitro
Planta Med; 57(2):125-8 1991
The root extract of Panax ginseng was investigated for its inhibitory effects on DNA synthesis, mutagenicity, and cellular transformation using V79 and NIH 3T3 cells. DNA synthesis measured by the [3H]thymidine incorporation into V79 Chinese hamster lung cells was significantly decreased by the addition of ginseng extract (0-1 microgram/ml) to the medium. However, ginseng extract was found to increase the rate of DNA excision repair synthesis in V79 cells in response to treatment with UV radiation or methyl methanesulfonate. The extract also showed decreased mutation frequency when mutagenicity was examined using V79 cells at the hypoxanthine-guanine phosphoribosyl transferase locus as resistance to 6-thioguanine after exposure to methyl methanesulfonate. We also found that the components of ginseng extract continue to exert an inhibitory effect on the transformation of NIH 3T3 cells initiated by 3-methylchloanthrene, methyl methanesulfonate, and 1-methyl-3-nitro-1-nitrosoguanidine.
radiation injury by ginseng-some properties of the radioprotective substances
J Radiat Res (Tokyo); 22(3):336-343
Some properties of the radioprotective substance ginseng extract (GE) were studied in male 4-wk-old JCL-ICR mice. Prior to injection GE was dissolved in physiological saline and insolubles discarded after centrifugation. Mice injected with only physiological saline served as controls. The 30-day survival ratio was measured in both groups. Methanol-soluble GE did not protect the irradiated animals. Acid or alkali (0.12 N) inactivated GE at 60 C. GE radioprotective activity was stable after heating in physiological saline at pH 7 in a boiling-water bath for 15 min. GE was separated into two fractions by CM-cellulose column chromatography. Fraction CM-A was significantly efficacious at p less than 0.05, and CM-B was effective at p less than 0.001; doses were proportional to yield. UV spectrum and biuret tests suggested the presence of protein in the CM-B fraction. Supernatant obtained after heating the CM-B solution at pH 7 was separated into fractions G-I, G-II, and G-III by gel chromatography with a Sephadex G-75 column. G-I (0.44 mg/animal) and G-III (0.84 mg/animal) were significantly efficacious, but G-II (0.47 mg/animal) was not. The active component in ginseng had been thought to be ginseng saponin. Examination of the methanol-soluble fraction showed that the radioprotective component of GE is not saponin. Purification of the radioprotective substance is needed to clarify the chemical structure.
J Radiat Res (Tokyo); 22(3):323-335
The radioprotective effect of ginseng extract (GE) in JCL-ICR mice and hematological recovery of irradiated native and splenectomized mice were studied. Six-wk-old male mice were irradiated with 720 or 550 R. Within 3 min after irradiation, mice were injected ip with GE dissolved in 0.2 ml physiological saline. Control mice were injected only with saline after irradiation. Injection of 5.0 mg GE 2.5 hr before or after exposure to 720 R was significantly efficacious, but injection 1 day after treatment was not. Administration of 5.5 mg GE 2 or 1 day prior to irradiation was more efficacious than administration immediately after irradiation. The 30-day survival ratio of mice irradiated with 720 R was 5, 45, 75 and 82.5% for mice injected with 0, 1.8, 3.4, and 6.8 mg GE, respectively. The difference between control and GE groups was significant. Splenic wt of irradiated mice decreased to approx 1/3 normal on days 2-10 in the control group. The decrease was less in the GE group. Thymic wt decreased after irradiation by approx 30% from day 0 to day 30. Recovery of thymic wt was not stimulated by GE extract. GE-stimulated recovery of splenic DNA, and of thrombocyte and erythrocyte counts was observed; GE did not markedly affect leukocyte counts. GE increased the 30-day survival ratio of splenectomized mice. Only thrombocyte counts after exposure were stimulated by GE in splenectomized mice.
Recovery of thrombocyte counts after exposure
is assumed to be one of the most important factors in restoration after bone
marrow death.Substances stimulating recovery from radiation injury
Radioisotopes; 27(11):666-675 1978
Studies on radiation damage and recovery, and on substances that stimulate recovery are reviewed. Separation and testing of active extracts from the root of Panax ginseng, which stimulate recovery from radiation damage in mice are described. Various doses of ginseng extract (GEX) were given (mostly ip) to JCL-ICR mice (6 wk old; 40 mice per group), immediately after irradiation (IR) at various levels. The effects on the 30-day survival rates were studied. At a GEX dose of 6.8 mg and an IR dose of 720 R, the 30-day survival rate was 82.5%. At a GEX dose of 5.0 mg, no significant differences in the 30-day survival rate were found, whether GEX was injected ip or iv. At a GEX dose of 5.8 mg and an IR dose of 550 R, improvement began about the 10th day (WBC, RBC, platelet count). In non-irradiated mice, there was no particular effect of GEX on the blood. In mice splenectomized 1 wk before IR (770 R), 6.0 mg of GEX improved the 30-day survival rate compared with saline treated controls. The WBC and RBC did not recover in splenectomized mice that were irradiated, but the platelet count increased. A marked increase in the spleen wt of non-irradiated mice, associated with the administration of GEX, was eliminated by a final heat treatment of extract liquor and removal of the precipitant. Administration of 5.0 mg GEX was most effective in increasing the 30-day survival rate when given 1-2 days before irradiation. The administration of GEX 24 hr after irradiation resulted in a 30-day survival rate compared with that of controls.
Acemannan Immunostimulant in
combination with surgery and radiation therapy on spontaneous canine and feline
J Am Anim Hosp Assoc; 31(5):439-47 1995
Eight dogs and five cats with histopathologically confirmed fibrosarcomas were treated with Acemannan Immunostimulanta in combination with surgery and radiation therapy. These animals had recurring disease that had failed previous treatment, a poor prognosis for survival, or both. Following four to seven weekly acemannan treatments, tumor shrinkage occurred in four (greater than 50%; n = 2) of 12 animals, with tumors accessible to measurement. A notable increase in necrosis and inflammation was observed. Complete surgical excision was performed on all animals between the fourth and seventh week following initiation of acemannan therapy. Radiation therapy was instituted immediately after surgery. Acemannan treatments were continued monthly for one year. Seven of the 13 animals remain alive and tumor-free (range, 440+ to 603+ days) with a median survival time of 372 days. The data suggests that Acemannan Immunostimulant may be an effective adjunct to surgery and radiation therapy in the treatment of canine and feline fibrosarcomas.
NOVEMBER 27, 1997
By Lauran Neergaard
WASHINGTON -- Thousands of patients with an incurable type of non-Hodgkin's lymphoma won their first new weapon in a decade Wednesday.
The Food and Drug Administration approved a novel, genetically engineered drug to attack the immune system cancer with far fewer side effects than standard treatment.
Rituxan is not a cure, but the FDA said it has an "excellent" success rate in shrinking tumors safely.
The approval makes Rituxan the nation's first anti-cancer monoclonal antibody -- a long-awaited biotherapy in which specially manufactured antibodies bind to cancer cells and trigger the immune system to do the killing instead of toxic chemicals.
One patient who tested Rituxan called the approval "something to celebrate this Thanksgiving."
"Even though my type of lymphoma is still considered incurable, Rituxan has renewed my hope of raising my three children," said Dr. Wendy Harpham, a Richardson, Texas, physician who failed other treatments before Rituxan therapy put her cancer in remission.
About 240,000 Americans have non-Hodgkin's lymphoma, a cancer of the lymph system that targets vital white blood cells. Many patients are successfully treated. But about half of them have an incurable form called low-grade non-Hodgkin's that causes repeat relapses over six or seven years.
These patients try high doses of chemotherapy, radiation and bone marrow transplants that can cause severe side effects, particularly when these treatments also kill healthy cells that get in the way.
Rituxan, on the other hand, is made from a genetically engineered mouse antibody designed to be a more specific treatment. Scientists don't know exactly how it works, said FDA monoclonal antibody chief Kathryn Stein. But ultimately these antibodies zero in on the white blood cells involved in non-Hodgkin's lymphoma and trigger their death.
"This is the first of what we hope will be many monoclonal antibodies for tumor treatment," she said.
In a study of 166 patients with advanced cancer, 48 percent had their tumors shrink by at least half. Six percent of patients had complete remissions. Half the successful patients remained stable for more than 11 months, a rate that Stein called "excellent."
Rituxan therapy does not require hospitalization. Manufacturers IDEC Pharmaceuticals and Genentech Inc. say Rituxan, known chemically as rituximab, will be available within a month. A complete course of four weekly transfusions will cost roughly $9,000, comparable to many chemotherapies.
Rituxan has some risks. It can kill healthy white blood cells as well as cancerous ones, meaning patients could suffer infections although no unusual rates have appeared so far, said Dr. Peter McLaughlin of the M.D. Anderson Cancer Center, the drug's lead investigator. Those cells grow back on their own within a year.
Additionally, most patients have temporary and mild flu-like symptoms, such as fever and chills, one to two hours after the first infusion, as their bodies learn to recognize the new antibody, he said.
So few side effects make Rituxan a prime candidate to give to lymphoma patients in addition to chemotherapy, hoping for a one-two punch against the disease, McLaughlin said. Doctors already are studying how well such a combination could work, as well as the feasibility of giving it to earlier patients instead of waiting until they relapse.
But for patients today, Rituxan promises to buy some time. Harpham says if she hadn't gotten to test the drug, she would already have tried her last option -- a bone marrow transplant that she still can turn to if she has another relapse.
Still, "Rituxan has been the closest answer to my prayers so far," she said.
LE Magazine September 2000
Polyunsaturated n-3 fatty acids, such as
those found in various fish oils, have demonstrated their ability to slow
down the development of tumors and their metastasis. In addition, researchers
have recently found that these fatty acids may also help to prevent cachexia
(the muscle wasting and weight loss that occurs in some cancer patients
irrespective of proper nutritional intake). Controlling cachexia may
subsequently increase the efficacy of drug cancer therapies, improve quality
of life, and extend the remission periods for patients, be they pets or
humans. Past research has already documented that cachexia is associated with
extreme changes in carbohydrate, protein and lipid metabolism, which give
rise to anorexia, fatigue, immune compromise and weight loss. Cachexia is
believed to compromise patients' quality of life, survival time, as well as
limiting their response to treatment.
Life Extension Foundation
Thursday, December 27, 2001
TO: The physician treating _______________(Type in your name here)
RE: Adjuvant drug therapy for cancer patients
Our non-profit organization has uncovered evidence that suggests two prescription drugs may be of significant value in treating cancer in addition to other therapies. Here is an excerpt from a research report we published in 1999:
Cancer cells often produce large amounts of the enzyme cyclooxygenase-2, abbreviated COX-2. This enzyme acts as a biological fuel by causing rapid cell division. An article in the journal Cancer Research (1999 Mar 1; 59 (5) showed that COX-2 levels in pancreatic cancer cells are 60 times greater than in the adjacent normal tissue.
According to a study in the British Journal of Cancer (1997;75 (8), human prostate cancer cells sustain their growth by stimulating themselves to up-regulate their production of COX-2, which facilitates cell proliferation via several mechanisms. However, COX-2 inhibition results in a decrease in cell replication and a reduction in the synthesis of COX-2 and its metabolites, such as the dangerous prostaglandin E2. The authors of this study concluded that COX-2 is involved in the maintenance of growth and homeostasis of human prostate cancer cells.
In the Sept 7, 1999 issue of the Wall Street Journal, an investigative report revealed that scientists are actively investigating COX-2 inhibitors as drugs that would be effective in the prevention and treatment of many cancers. COX-2 inhibiting drugs, given to small numbers of patients with colon polyps (pre-cancerous lesions), caused the completely disappearance of the lesions. When a group of rats were given a potent carcinogen, there was a 90% reduction in those, who developed cancer if they were on COX-2 inhibition therapy. In the few rats that did develop the tumors while taking COX-2 inhibition therapy, the tumors were 80% smaller and less numerous than the group not on COX-2 inhibition therapy. The Wall Street Journal revealed that a handful of physicians, knowledgeable about COX-2 and cancer, are prescribing COX-2 inhibitors to their patients.
In a report published in JAMA (1999 Oct 6;282(13), a nearly 10 year epidemiological study showed that COX-2 expression in colorectal cancer was significantly related to survival. The doctors concluded that the data add to the growing epidemiological and experimental evidence that COX-2 may play a role in colorectal tumorigenesis".
The Life Extension Foundation predicts that COX-2 inhibiting drugs will eventually be approved to treat cancer, but in the meantime, we are requesting physicians to look into the matter and consider prescribing a COX-2 inhibiting drug as an adjuvant cancer therapy. The COX-2 inhibitory drug of choice will be described later in this article. But first we want to briefly discuss another prescription drug that may also benefit cancer patients:
The protein products of res genes normally participate in the signal transduction cascade of sending messages from the cell surface to the nucleus. In addition, the Ras family of oncoproteins can modulate the transduction of signals of cancer cell growth, proliferation and metastasis. Mutations in genes encoding Ras proteins have been intimately associated with unregulated cell proliferation in a number of different kinds of cancers, e.g., leukemia, brain tumors, breast and pancreatic cancers.
The "statin" class of cholesterol-lowering drugs has been shown to inhibit the activity of RAS oncogenes. Some of the "statin" drugs that have shown efficacy are lovastatin, simvastaton, and pravastatin.
There are mechanisms other than inhibition of RAS oncogene activity that make the "statin" drugs attractive as adjuvant anti-cancer agents. According to a study in The Journal of Biological Chemistry (1998, Vo. 273, No.17), prostate cancer cells are very sensitive to the induction of growth arrest and cell death by lovastatin. This study showed that lovastatin was particularly effective to induce prostate cancer cell G1 DNA replicative phase arrest and cell death in human androgen-independent (hormone-refractory) lines. This study is confirmed by other studies, which showed that "statin" drugs interfere with critical growth pathways that enable cancer cells to proliferate out of control.
A suggested combination therapy to inhibit COX-2 and provide "statin" regulatory control of cell hyperproliferation is as follows:
Lodine XL, an FDA approved arthritis drug, interferes with COX-2 metabolic processes. The maximum dosage for Lodine is 1,000 mg daily. The most convenient dosing schedule for the patient involves the prescribing of two Lodine XL 500 mg tablets in a single daily dose. As with any nonsteroidal anti-inflammatory drug (NSAID), extreme caution and physician supervision is a required. The most common complaints associated with Lodine XL use is related to the gastrointestinal tract. Serious GI toxicity such as perforation, ulceration, and bleeding can occur in patients treated chronically with NSAID therapy. Occasionally serious renal and hepatic reactions have been reported. Lodine XL should not be given to patients, who have previously shown hypersensitivity to it, or in whom aspirin or other NSAID's induce asthma, rhinitis, urticaria, or other allergic reactions. In such cases, even fatal reactions may be the consequence of NSAID administration.
Nimesulide is a safer COX-2 inhibitor, however, it is not approved by the FDA. It is available from Mexican pharmacies, or can be ordered by mail from European pharmacies. The suggested dose for nimesulide is two 100 mg tablets a day. The Life Extension Foundation recommended nimesulide as an adjuvant cancer therapy in 1997. Unfortunately, only a few members could obtain it because the FDA's seizure of personal use unapproved drug importation.
The two newest COX-2 inhibitors are Celebrex and Vioxx, but we suggest that cancer patients consider other drugs that have a more predictable safety history. Suppression of COX-1 is associated with the severe gastrointestinal complications induced by NSAIDs in humans, whereas selective inhibition of COX-2 reduces this side effect risk. It seems that it is the COX-2 enzyme that fuels cancer cell proliferation, so the objective of choosing the proper NSAID in the treatment of cancer is to find one that suppresses the minimum percentage of COX-1 and maximum COX-2. Said differently, it is critical to not overly suppress COX-1 because the digestive tract needs it to maintain its structure, whereas it is important to suppress COX-2 because it is, amongst the other factors, an enzyme that cancer cells use to multiply.
In a meticulous study published in the Proceedings of the National Academy of Sciences (1999;Vol 96), Lodine (etodolac) was compared with other nonsteroidal antinflammatory (NSAID) drugs, including Celebrex and Vioxx, to assess its effect on suppressing COX-1 and COX-2. This study showed that Lodine caused an 80% suppression of dangerous COX-2, while only inhibiting 25% of the important COX-1. This study showed that Lodine was slightly more effective than Celebrex in suppressing COX-2, and slightly less effective than Vioxx.
A novel treatment approach would be to combine a COX-2 inhibitor with a "statin" drug such as Lovastatin. A study published in the journal, Gastroenterology (1999, Vol.116, No. 4, Supp A369) showed that Lovastatin augmented by up to five-fold, the cancer cell killing effect of a drug with COX-2 inhibiting properties (Sulindac). In this study, three different colon cancer cell lines were killed (made to undergo programmed cell death) by depriving them of COX-2. When Lovastatin was added to the COX-2 inhibitor, the kill rate increased by up to five fold.
We thus suggest that physicians consider prescribing a COX-2 inhibitor and a "statin" drug to cancer patients, in addition to other conventional and integrative therapies, for a period of three months. Here is a suggested doing schedule:
Blood tests to assess liver and kidney function are critical in protecting against potential side effects. To ascertain efficacy, regular serum tumor marker testing (such as the CEA, PSA, CA 19.9 depending on the typr of cancer) and imagery scanning is suggested.
Scientific abstracts substantiating this aggressive adjuvant approach to treating cancer can be found at the Foundation's Website (www.lef.org). cancer update abstracts
Why ‘Eat your fruits and vegetables' is good advice
by Daniel J. Bourassa, D.C.
Beta-sitosterol is one more reason why your grandmother was right when she instructed you to "eat your fruits and vegetables." Beta-sitosterol, one of the main subcomponents of a group of plant sterols known as phytosterols, is a white, waxy substance. While beta-sitosterol has a chemical structure that is very similar to that of cholesterol, it is only manufactured by plants, not by mammals. In fact, beta-sitosterol is found in many plant oils we use on a daily basis, such as corn and soy oil. Unfortunately, the average American diet provides only 200 to 300 mg of beta-sitosterol per day—far less than the optimum levels required for health benefits, according to one authority.(1) Research into beta-sitosterol has shown beneficial effects against a wide variety of human ailments.
For the last 30-plus years, beta-sitosterol has been known to safely reduce cholesterol levels. Beta-sitosterol's close chemical resemblance to cholesterol allows it to be incorporated into mammal cellular membranes, thereby blocking the absorption of cholesterol by competitive inhibition. Though beta-sitosterol is not well-absorbed by the body (5-10%), when consumed with cholesterol it effectively blocks cholesterol's absorption, resulting in lower serum cholesterol levels. Beta-sitosterol has also been shown to favorably influence lipoprotein (HDL, LDL) profiles.
Promoting Prostate Health
Dr. Ward Dean previously described a number of herbal preparations shown to help prevent and treat prostate problems like benign prostatic hyperplasia (BPH).(2) These herbs include saw palmetto extract, Pygeum africanum, and stinging nettle. Pumpkin seeds are also often used and are occasionally beneficial in BPH.(3)
In Europe, herbal preparations are often considered prescription drugs (Permixon-saw palmetto, Tadenan-Pygeum africanum, Azuprostat-beta-sitosterol). These plant sterols improve prostate symptom scores, improve quality of life, and reduce urine volume and residual urine levels. Incredibly, they exert these apparent benefits without reducing the size of the prostate! Beta-sitosterol—alone or as a constituent of one of the other herbs—is one of the major active constituents in these herbal preparations. Indicative of the high regard in which beta-sitosterol is held, one research team reported that "beta-sitosterol itself is an effective option in the treatment of BPH."(4)
A number of studies have indicated that beta-sitosterol may have powerful anti-cancer properties as well. Beta-sitosterol was found to reduce growth of human prostate(5) and colon cancer cells,(6) and displayed antitumor activity against lymphocytic leukemia.(7)
In this regard, it is widely accepted that diets high in vegetables and fruits result in lower incidences of cancer of all types. Diets high in soy have long been associated with anticancer benefits in many organ systems, and low cancer mortality rates. Beta-sitosterol appears to be one of the key compounds in soybeans that suppresses carcinogenosis.(8)
Beta-sitosterol may give a boost to athletes involved in endurance sports. Marathon runners and endurance athletes often suffer from immune suppression and reduced inflammatory response during intense training periods and post event. Beta-sitosterol has been shown to prevent this breakdown in the immune system.(9) Beta-sitosterol was also noted to enhance lymphocyte proliferation and NK-cell activity.(10) This enhancement of the immune system should be of benefit to anyone wishing to boost their immune status, specially during times of physical stress or active disease process.
Normalizes Blood Sugar
Beta-sitosterol has been shown to normalize blood sugar and insulin levels in Type II diabetics. The mechanism for this effect is that beta-sitosterol-3-beta-D-glucoside stimulates the release of insulin in the presence of non-stimulatory glucose concentrations,(11) and inhibits glucose-6-phosphatase.(12) The significance of this is that in the liver, the enzyme glucose-6-phosphatase is the primary pathway for conversion of dietary carbohydrates to blood sugar. Glucose-6-phosphatase dephosphorylates glucose-6-phosphate to yield free D-glucose. Free D-glucose then passes into the blood, elevating blood sugar levels. Slowing the rise of blood glucose levels by down-regulation of glucose-6-phosphatase helps delay the age-related worsening of glucose tolerance and delay the onset of Type II (maturity onset) diabetes.
Other Benefits of Beta-sitosterol
An extensive review of the scientific literature cites studies showing beta-sitosterol's anti-viral, anti-bacterial and anti-fungal actions, and ability to relieve inflammation, heal ulcers, and enhance uterine tone and alleviate cramps.(1) There is even a Japanese patent for beta-sitosterol as a treatment for baldness!
Research has shown that beta-sitosterol is an effective adjunct in the support of benign prostatic hypertrophy. For those already taking supplement formulas for BPH (ProstaCol, Pygeum africanum, Saw Palmetto Extract, Stinging Nettle, etc.), who may not experience the full range of positive results these herbal extracts have been proven to exhibit, the addition of beta-sitosterol should be considered.
Research also supports a role for beta-sitosterol as an agent to safely lower cholesterol and improve cardiovascular performance, and for the management of blood sugar levels. Additionally, beta-sitosterol has been shown to support immune enhancement for athletes and in instances where increased immune response is desired, such as in cancer and infectious diseases, including TB and HIV. Mason recommends 300 mg supplement per day, although there have been no reports of toxic effects at any dosage.
1. Mason R, Beta-sitosterol -the "Natural Prostate Miracle"; Young Again Products, DTM, Inc., NY It has been proposed that the plant extracts (including beta-sitosterol) exert their effects as 5 alpha-reductase inhibitors, similar to the prescription drug Finasteride. 5 alpha-reductase is the primary pathway in the conversion of testosterone to dihydrotestosterone (DHT)—testosterone's active form.
2. Dean, W, Benign Prostatic Hypertrophy, Near-Universal Malady in Men over 50. Vitamin Research News, Aug, 1998.
3. Bracher, F., Phytotherapy of benign prostatic hyperplasia. Urologe A 1997 Jan;36(1):10-17.
4. Klippel K. F., et al., A multicentric, placebo-controlled, double-blind clinical trial of beta-sitosterol (phytosterol) for the treatment of benign prostatic hyperplasia. German BPH-Phyto study group. Br J Urol 1997 Sep; 80(3): 427-32.
5. von Holtz RL, et. al., beta-Sitosterol activates the sphingomyelin cycle and induces apoptosis in LNCaP human prostate cancer cells. Nutr Cancer 1998;32(1):8-12.
6. Awad AB, et al., beta-Sitosterol inhibits growth of HT-29 human colon cancer cells by activating the sphingomyelin cycle. Anticancer Res 1998 Mar-Apr;18(2A):1227
7. Miles DH, Kolpol U, Tumor inhibitors II: constituents and antitumor activity of Sarracenia flava. Journal Pharm Sci 1976 Feb;65(2):284-5.
8. Kennedy AR, et al., The evidence for soybean products as cancer preventive agents. Journal of Nutrition 1995 Mar;125(3 Suppl):733S-743S.
9. Bouie PJ, et al., The effects of B-sitosterol (beta-sitosterol) and B-sitosterol glucoside (beta-sitosterolG) mixture on selected immune parameters of marathon runners: inhibition of post marathon immune suppression and inflammation. Int Journal Spots Med 1999 May;20(4):258-62.
10. Bouie PJ, et al., beta-Sitosterol and beta-sitosterol glucoside stimulate human peripheral blood lymphocyte proliferation: implications for their use as an immunomodulatory vitamin combination. Int J Immunopharmacol 1996 Dec;18(12):693-700.
11. Ivorra MD, et al., Effect of beta-sitosterol-3-beta-D-glucoside on insulin secretion in vivo in diabetic rats and in vitro in isolated rat inslets of Langerhans. Pharmazie 1990 Apr;45(4):271-3.
12. Rahman, et al. in Pure Applied Chemistry 1994.
by Karen Kaufman, MS, CCN
COX-2 inhibitors are members of a class of drugs that have been heavily advertised and promoted for osteoarthritis. The best known of these drugs are celecoxib (Celebrex) and rofecoxib (Vioxx). They are considered a better or 'super' version of the traditional Non-steroidal Anti-Inflammatory drugs (NSAIDs). NSAIDs include aspirin, ibuprofen, and naproxen. NSAIDs all effectively reduce inflammation and thereby relieve pain by inhibiting substances that promote inflammation. Among these "mediators" of inflammation are prostaglandins, which are produced through the cyclo-oxygenase 1 and 2 (COX-1 and COX-2) enzyme systems. Prostaglandins are over-expressed in inflammation, but certain prostaglandins are beneficial and protective.
NSAIDs and Side Effects
A problem with NSAIDs is their potential for serious side effects. The most notable side effects occur within the GI tract. NSAIDs block the production of the "good" prostaglandins that help maintain the protective mucosal lining of the stomach. Many of the people dealing with the chronic pain of arthritis have to ride a seesaw. The NSAIDs reduce the burning pain in their joints, but leave them feeling like they have a whole in their stomach. The NSAIDs also put arthritis sufferers at risk for a sudden, symptom-less, life-threatening GI bleeding.
Lower Cancer and Alzheimer's
Because arthritis afflicts such a huge segment of the older population, millions of people take NSAIDs daily to alleviate their pain. As a result, physicians have noted that people who take these medications routinely for years for arthritis often have a lower incidence of other diseases of aging, such as Alzheimer's disease (AD) and colon cancer. Some epidemiologists speculated that the drug was not affecting the disease process of colon cancer itself, but was only causing a higher incidence of bleeding in the colon or rectum, which resulted in the cancer being detected earlier. In the case of Alzheimer's, speculation focused on the possibility that the brain deterioration occurred in part because of some sort of inflammatory process, and was inhibited by the anti-inflammatory effects of the NSAIDs. Nevertheless, physicians have generally avoided recommending the routine prophylactic use of NSAIDs to prevent Alzheimer's or certain colon/rectal cancer because of the potentially serious side effects mentioned above.
Selective COX-2 Inhibitors
Enter the new selective COX-2 inhibitors. Selective COX-2 inhibitors have recently become the subject of much interest and research for their potential role in preventing AD or colon cancer, due to their ability to inhibit the "bad" prostaglandins that are created through the COX-2 enzyme system, but do not inhibit the "good" prostaglandins that are created through the COX-1 enzyme system. Scientists have found an over-expression of COX-2 in plaques in the brains of people with AD. In addition, there is an over-expression of COX-2 in colon and pancreatic tumor cells. The COX-2 inhibitors seem to have eliminated the deleterious effects on the GI tract. However, they still seem to have negative side effects similar to the NSAIDs with regard to the kidneys. Some people who take these drugs experience an increase in blood pressure as well as a tendency to retain fluid. These can become serious issues, particularly in an aging population.
Considering the beneficial effects of the COX-2 inhibitors, it would be wonderful to find a substance that acts as a COX-2 inhibitor without the harmful side effects seen in pharmaceutical drugs. It appears that just such a substance -- the common spice turmeric (Curcuma longa) -- possess such properties. According to results of a study in the UK, turmeric was found to inhibit the production of COX-2. This may explain why so many people experience relief from arthritis pain by taking substantial doses of turmeric. In fact, the Arthritis Foundation's Guide to Alternative Therapies, (page 229) by Judith Horstman, acknowledges that there may well be some anti-inflammatory properties in turmeric that can be beneficial to arthritis sufferers.
The information in this article is not intended to provide personal medical advice, which should be obtained from a medical professional, and has not been approved by the U.S. FDA.
Copyright 2001 by Vitamin Research Products, Inc. (VRP) The use of information found in Vitamin Research News for commercial purposes is prohibited without written permission from VRP.
Studies Reinforce Benefits
by Don Chaddock
Isn't it nice to know that your mother was right? Eating cruciferous vegetables such as broccoli, cauliflower and brussels sprouts is good for you, but you'd have to eat a whole lot of it to achieve results researchers have been getting.
Found in such vegetables is a powerful phytonutrient called DIM, or diindolylmethane. Like broccoli? To get just 10 to 30 mg of DIM you'd need to eat one-and-a-half pounds of it. While 30 mg is better than none, it's not therapeutic. Michael Zeligs, MD, recommends people take 100 to 200 mg of "bioavailable" DIM daily. (1) To get this amount from food just isn't practical, you'd require four to six pounds of broccoli to achieve beneficial levels.
Over 25 Years of Research
DIM is nothing new. Researchers have long known about its numerous anti-cancer benefits. In 1975, DIM was identified as a naturally-occurring indole that affects the metabolism of chemical carcinogens. The researchers also went so far as to conclude DIM could play a critical role in the body's response to environmental carcinogens. (2)
Other studies reinforce DIM's ability to protect against environmental cancer-causing elements. A later in vitro study at Oregon State University showed that DIM inhibited the metabolism of aflatoxin B1, a food contaminant and potent carcinogen. (3)
Can DIM Kill Cancer Cells?
DIM's anti-cancer properties have been studied thoroughly by researchers worldwide. In 1996, scientists for Israel's Department of Food Engineering and Biotechnology discovered that DIM actually induced apoptosis (programmed cell death) in human cancer cells. (4)
DIM's ability to inhibit tumor formation was studied as early as 1978. Researchers administered an anti-cancer cocktail of DIM and indole-3-carbinol to female rats 20 hours prior to chemically-inducing mammary tumors. They found that the combination had an inhibitory effect on tumor growth. (5)
A 1999 study on human breast cancer cells found that DIM blocked estrogen receptors without the presence of estradiol and even inhibited the growth of estrogen-dependent cancer cells. Researchers concluded that DIM possessed anti-estrogenic properties. (6)
Weight Loss and Workouts
According to Zeligs, supplemental use of DIM promotes higher levels of good estrogen, which promotes fat-burning for energy. (7) He recommends women take up to 300 mg of DIM daily for this purpose. (1) Men engaged in exercise training programs may also find 300 to 400 mg daily helpful. (7,1)
DIM has been studied for more than 25 years. Its estrogen balancing and anti-cancer properties, especially for prevention, have been well-documented. All this, teamed with the apparent fat-burning ability of DIM, only leads us to conclude that DIM is safe, effective and has many potential uses.
1. Challem, J. "DIM: The New Hormone Balancer", Let's Live, 2000 May; 56.
2. Wattenberg, L.W. Effects of dietary constituents on the metabolism of chemical carcinogens. Cancer Res, 1975 Nov; 35(11 Pt. 2): 3326-31.
3. Stresser DM, Bjeldanes LF, Baily GS, Williams DE. J Biochem Toxicol, 1995 Aug:10(4):191-201.
4. Ge X, Yannai S, Rennert G, Gruener N, Fares FA. 3,3'-Diindolylmethane induces cell apoptosis in human cancer cells. Biochem Biophys Res Commun, 1996 Nov 1;228(1):153-8.
5. Wattenberg LW, Loub WD. Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res, 1978 May;38(5):1410-3.
6. Chang YC, Rilby J, Chang GH, Peng BC, Firestone G, Bjeldanes LF. Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3,3'-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. Biochem Pharmacol, 1999 Sep 1;58(5):825-34.
7. Zeligs M, Connelly AS. All About DIM. Penguin Putnam Inc., New York, NY, 2000; 14-18
"Chinese medicine and pharmacology are a great treasure house. Efforts should be made to explore them and raise them to the highest level." -- Mao Tse-tung
The use of herbs as medicines has been practiced for centuries, in virtually every culture in the world. Native American medicine relied heavily on the use of herbs, and traditional herbal remedies are still commonly prescribed in Eastern countries such as China, Korea, and Japan. Trial and error led to the development of folk medicines, and the most effective remedies were passed down through generations. Herbs have been used to treat nearly every known affliction and disease. While some herbs have been shown to be ineffective, others have stood the tests of time and research, proving their worth. Two such herbs that are widely used, and have been thoroughly researched for their immune boosting properties, are Echinacea and Astragalus.
Echinacea, or the Coneflower, as it is more commonly known to gardeners, is native to North America, and played an important role in Native American medicine. Numerous tribes used it to treat a variety of symptoms and diseases, including: sore mouth and gums, toothache and coughs, and as an anti-inflammatory and antiseptic agent.
The earliest reference on Echinacea for medical purposes is from 1763, by L.T. Gronovius, who stated that E. purpurea bears a sharp-tasting root and is very valuable in treatment of saddle-sores of horses. However, little, if any, research on applications for humans was performed until the 1830s, when Dr. H.C.F. Meyer, who had made note of the use of Echinacea by the Native Americans, brought it to the attention of John Lloyd, a pharmacist.
Numerous Echinacea-based formulas were produced by Meyer and Lloyd, as well as other pharmaceutical companies, guaranteed to cure a long list of ailments, including: rheumatism, migraine, infection, eczema, tumors, syphilis, gangrene, typhoid, malaria, diphtheria, hemorrhoids, snake bites and bee stings. Echinacea extracts were commonly prescribed until the introduction of sulfa drugs in the 1930s, at which point it faded into relative obscurity in America. Luckily, research on its medicinal uses continued in Europe; hence, most of the early research on Echinacea is from Germany.
In the earlier part of this century, Echinacea was still being touted as a cure-all. An excerpt from an herbal book originally printed in 1931 states that "Echinacea increases bodily resistance to infection, [and can be used for treating] boils, septicemia, cancer, syphilis, blood impurities [and is] useful as a strong alternative and aphrodisiac." Interestingly, many of these claims still hold true (although its role as an aphrodisiac has yet to be proven!). Modern indications for the use of this versatile herb include: prevention and treatment of viral infections such as the common cold, influenza, herpes, and bronchitis. Echinacea can also be used to treat arthritis (as an anti-inflammatory agent) and allergies.
Echinacea is actually a species of flowers, and as such, comes in a variety of colors, shapes, and potencies. Studies examining its influence on immune cell proliferation, antibody production, and antiviral activities have demonstrated that E. purpurea is the most potent of the varieties.
Mechanisms of Action
The roots of E. purpurea contain arabinogalactans, which have been shown to play a major role in the immunostimulating activities associated with this plant. These compounds provide a protective effect against viral infection. Numerous in vitro and in vivo studies have documented the antiviral effects of Echinacea. For example, when peripheral blood leukocytes from healthy volunteers were infected with Candida albicans (a yeast), the cells incubated with Echinacea extracts initiated an acute phase response, and phagocytosis was activated much sooner than in cells without the Echinacea.
Another in vivo study demonstrated that treatment of mice with Echinacea extract results in induction of an increased proliferation of phagocytes in the spleen and bone marrow (when exposed to Listeria monocytogenes and Candida albicans). In other words, Echinacea treatment stimulated the immune response to decrease the chances of infection.
Echinacea and Cancer
Not only is Echinacea beneficial in the prevention of infection from viruses and bacteria, it is also beneficial in cancer therapies. In mice with impaired immune systems, when Echinacea was administered, resistance to infection was restored to normal levels (compared to healthy mice).
Studies in humans have shown similar results. For example, patients with inoperable liver cancer, who were receiving a combination of cyclophosphamide (a toxic chemotherapy drug) and thymostimulin (which induces the release of interleukin-2 and interferon) were treated with Echinacea. Subjects experienced a dramatic reduction in side effects associated with the chemotherapy, an enhanced quality of life, improved immune functions, and a significant rise in natural killer cell activity and CD-4 levels. Some of these protective effects are mediated by the increase in cytokine production, such as increased levels of tumor necrosis factor-alpha (TNF-() and interleukin-1 (IL-1).
Part II of this article, "Astragalus" will appear in our March 1996 newsletter.
The information in this article is not intended to provide personal medical advice, which should be obtained from a medical professional, and has not been approved by the U.S. FDA.
This article first appeared
issue of VRP's Nutritional News
by Yu Shao
Cancer: The word itself causes a strong reaction in most of us. It evokes images of a slow, painful death. Each year over 1.3 million Americans are diagnosed with cancer. Every minute one person dies from this disease. Traditional medicine offers us surgery, chemotherapy, and/or radiation as treatments. But these painful, toxic and sometimes even cancer-causing treatments only offer a less than 33% cure rate.
Are there any ways we can prevent and fight cancer? Statistical data shows us that about 60% of women's cancers and 40% of men's cancers are related to nutritional factors. At least 40% of cancer patients die from malnutrition, not from the cancer itself. Based on numerous scientific studies, cancer researchers around the world have begun to believe that certain natural nutrients can prevent and sometimes cure cancer. This gives new hope for those suffering from cancer.
History of The Magic Fish Oil
Interest in the potential benefits of fish oils emerged from the observation that cardiovascular diseases and cancer incidence rates are generally low in the Eskimos of Alaska and Greenland. (1, 2) These populations eat a diet high in fish fat and low in carbohydrates this is contrast to the diets of North American and other western populations who also consume a high fat diet but mostly from animal and vegetable oils.
Animal fats contain saturated fatty acids. Vegetable oils, like corn oil and safflower oil, contain high levels of polyunsaturated fatty acids of omega-6 type. Because a high intake of animal fat is related to an increased risk of heart disease, and intake of polyunsaturated fatty acids (such as corn oil) can lower cholesterol levels (believed to be beneficial to heart disease prevention), Americans tend to consume more vegetable oil than animal fats.
Researchers found that fish oil can significantly inhibit cholesterol production. The beneficial effects of fish oils come from their unique composition of high levels of the omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Additionally, these omega-3 polyunsaturated fatty acids can increase the HDL (so-called good cholesterol) levels. Fish oil also provides anti-inflammatory and anti-aggregatory effects which play a crucial role in the formation of atherosclerosis and thrombosis. Due to these findings, it is believed that both healthy people and heart disease patients can benefit from fish oil supplementation.
Fish Oil And Cancer
One exciting aspect of fish oil is its significant inhibitory effects against various human cancers in animal models, including breast cancer, colon cancer, skin cancer, pancreatic cancer, prostatic cancer, lung cancer, larynx cancer, etc. (3-8) Unlike fish oil--which is high in omega-3 polyunsaturated fatty acids--fats that are high in omega-6 polyunsaturated fatty acids (like corn oil) can increase tumor growth. Using a chemical carcinogen-induced cancer model, researchers found that a high intake of fish oil significantly lowered the cancer incidence in animal studies as compared to animals fed either low-fat diets or high corn oil diets. (9) By implanting human tumors into immune-deficient mice, researchers have found that a high fish oil diet can slow tumor growth. (9) These results suggest that fish oil can be used for both prevention and treatment of cancer.
Proposed Mechanisms For Fish Oil's Tumor
Although there is no clear mechanism to explain fish oil's significant anti-cancer effects, researchers have uncovered several potential models of action:
1. Alteration of cell membrane composition. After ingestion, fish oil is easily incorporated into cell membranes (especially tumor cells), which changes the cell membrane composition. This alteration will change the cell's response to growth factor, hormones, antibodies, etc.
2. Inhibition of prostaglandin production. Prostaglandin can stimulate tumor cell growth. Fish oil can inhibit the enzyme responsible for prostaglandin synthesis called prostaglandin synthase. After a high intake of fish oil, prostaglandin (especially in the tumor cells) is decreased significantly, which in turn, slows tumor growth.
3. Immune system stimulation.
4. Hormone profile changes, which may provide important benefits for hormone -related cancers like breast cancer.
5. Tumor cell toxicity, probably by causing lipid peroxidation in the tumor cells.
Fish Oil And Metastasis
One of the big concerns in cancer treatment is metastasis, the process by which tumor cells spread from the primary location to distant parts of the body. Metastasis is increased by a high intake of omega-6 fatty acids (i.e., corn oil), but is inhibited by fish oil. Using an immune-deficient mouse implanted with human breast cancer, researchers found that feeding a high fish oil diet (23%) to the mice significantly reduced human breast cancer cell metastasis to the regional lymph nodes and lungs. (10) This indicates the significant beneficial effects of fish oil supplementation in cancer treatment.
Fish Oil And Cachexia
Over 40% of cancer patients died from cachexia, not from cancer itself. Cachexia is the malnutrition and wasting away caused by cancer. Cachectic patients are characterized by extreme weakness and emaciation. If we can overcome this cancer-induced malnutrition, we can potentially save or prolong the life of over 40% of cancer patients.
Researchers in England found that fish oil could significantly prevent cachexia in an experimental model. Feeding the animals a high fish oil diet (compared to either a low-fat diet or a high corn oil diet), significantly decreased the loss of body weight caused by cachexia, and at the same time, muscle mass was significantly increased. Additionally, fish oil showed a dramatic anti-cancer effect which was as effective as some chemotherapy drugs. The researchers concluded that fish oil could significantly prevent the cachexia caused by cancer, and at the same time, provide potent anti-cancer action. (11)
Fish Oil And Chemotherapy
Researchers at Allie M. Lee Cancer Research Laboratory at the University of Nevada, Reno first declared that fish oil supplementation may be of benefit in cancer chemotherapy. By using a human breast cancer model, they found that feeding the animals a high fish oil diet both slowed the tumor growth and increased the tumor responsiveness to chemotherapy drugs by altering the drug activating systems. They also found that a high fish oil diet can significantly protect the host animals against the toxicity of chemotherapy drugs. The researchers concluded that fish oil supplementation will provide a three-pronged attack on cancer:
1. A strong anti-cancer effect.
2. Protection from chemotherapeutic drug toxicity.
3. Cachexia prevention. (12,13)
As a dietary supplement, fish oil shows significant benefits in cancer prevention and treatment. Due to the high incidence of cancers and the relatively low levels of fish oil intake in North America, it is likely that most people can benefit from fish oil supplementation.
1. Bang, HO, Dyerberg, J, and Hjorne N. Acta Med Scand, 200: 69-73, 1976.
2. Neilsen, NH and Hansen JPH. J Cancer Res Clin Oncol. 98: 287-299, 1980.
3. Carroll KK. Lipids, 27:793-797, 1992.
4. Reddy BS. Lipids, 27: 807-813, 1992.
5. Rose, DP and Connolly, JM. Lipids, 27: 798-803, 1992.
6. Roebuck, BD. Lipids, 27: 804-806, 1992.
7. Begin, ME, et al. J Natl Cancer Inst, 77: 1053, 1986.
8. Booyens, J. IRCS Medical Science, 14: 396, 1986.
9. Welsch, CW. Cancer Res., 52: 2040s-2048s, 1992.
10. Rose, DP, Connolly, JM, and Liu, XH. Diet and Breast Cancer (ed. American Institute for Cancer Research), pp83-91, Plenum Press, New York, 1994.
11. Tisdale, M and Dhesi, JK. Cancer Res., 50: 5022-5026, 1990.
12. Shao, Y, Pardini, L and Pardini, RS. Cancer Res., 54:6452-6457, 1994.
13. Shao, Y, Pardini, L and Pardini, RS. Lipids, 30: 1035-1045, 1995.
Turning Back Cancer's Clock
January 2000 Newsletter
by Kimberly Pryor
The statistics are staggering. Last year in the United States, 563,100 people were expected to die of cancer—more than 1,500 people a day. Cancer is the second leading cause of death in the United States, exceeded only by heart disease. These statistics translate into a very real threat to us all.
For the past two decades, scientists have looked upon fiber almost as a panacea in the battle against cancer, particularly colon, mammary and prostate cancer. The nightly news has bombarded viewers with the latest research outlining fiber's protective role. Even the marketing divisions of cereal and oatmeal manufacturers jumped on the bandwagon, touting the fiber versus cancer studies in their advertisements. However, recent research reveals that scientists may have been led astray when it comes to the cancer-inhibiting benefits of dietary fiber. As new studies unfold, researchers are beginning to realize that there is an additional substance in dietary fiber that adds to its powerful effects against cancer. This heretofore little-known substance is a component of fiber called inositol hexaphosphate, also known as InsP6, IP6 or phytic acid.
IP6 occurs in foods that are rich in fiber—especially cereals and wheat bran, along with corn, soy beans, nuts (especially peanuts), oats, seeds and rice. IP6 has traditionally been considered an antinutrient due to its ability to interfere with the body's absorption of minerals such as iron, calcium and zinc. However, scientists have recently discovered that IP6 is a powerful antioxidant and chemopreventive agent.1-3
Researchers initially overlooked IP6 because it was obscured by its dietary carrier—fiber. Fiber is an important part of the anticancer arsenal. Scientists estimate that up to 70% of all cancer is attributed to diet.4 The typical low fiber Western diet has been linked to the development of colon, prostate and mammary cancers.5-6
For example, in the U.S., the rates of prostate cancer and postmenopausal breast cancer are 26 and 10 times higher than in China, respectively—a difference possibly due to the fact that Americans consume almost three times less cereal than the Chinese.7 In addition, one study of 37 countries found a link between high intake of cereal grains and low rates of colon cancer;8 and researchers at the George Washington University Medical Center discovered that wheat bran alone, or wheat bran plus psyllium, inhibits earlier phases of carcinogenesis.9
These studies are in contrast to other studies, however, which found no direct link between fiber consumption and colon cancer. For example, Danes have a much higher incidence of colorectal cancer than Finns, although both groups consume approximately equal amounts of dietary fiber. This variance between studies suggests that fiber isn't the sole factor responsible for the inhibition of carcinogenesis. Researchers are beginning to suspect that IP6 may be even more potent in preventing cancer than the fiber in wheat bran. Scientists determined that although both Scandinavian populations consume equal amounts of fiber, the lower-risk Finns consume food items with 20-40% more phytic acid (IP6) than the higher-risk Danes (Fig. 2).10-11
IP6—along with its lower phosphorylated forms, especially IP5—is present in virtually all mammalian cells.12 It is an offspring of the nutrient inositol, and consists of a myo-inositol ring and six symmetrically distributed phosphate parts [Fig. 1].
Scientists have confirmed IP6's existence within
cells, but its primary purpose is still unknown. Although IP6 has been called
one of nature's most powerful antioxidants, its role appears to be far more
extensive. It has been suggested that IP6 can regulate heart rate and blood
pressure, and may also serve as a neurotransmitter.13-16
Because IP6 is a highly charged molecule, scientists formerly thought it could not be transported inside the cell, and believed that absorption by organisms was impossible. The fact that IP6 might work intracellularly was also discounted. However, preliminary work began to indicate otherwise. In vitro studies show that malignant cells almost immediately begin accumulating IP6 intracellularly. Scientists also found that IP6 is absorbed through the stomach and upper small intestine within one hour after administration.
When cells accumulate IP6, something remarkable happens. Unlike most other anticancer agents, IP6 turns back the clock on the malignant cells, forcing them to revert to a non-cancerous state. This phenomenon has been observed in HT-29 human colon carcinoma cells. Malignant and premalignant cells of the colon and other epithelial cells express the tumor marker D-galactose-ß-[1 ‘3]-N-acetyl-D-galactosamine; this marker is absent on normal cells. Following IP6 treatment of malignant cells, the tumor marker was significantly suppressed, and in most cells the marker was completely absent. IP6 also caused a decreased rate of cell proliferation.17-18
IP6 Proposed Anticancer Mechanisms
IP6 exerts its effects on the body by controlling cell division. IP6 reduces the rate of cellular proliferation, both in vivo and in vitro, and has exhibited an ability to reduce DNA synthesis.19-21 Scientists have suggested that one way IP6 may exert this cellular control is by interfering with mineral absorption, since iron and other minerals are important in gene regulation.22 Studies have shown a possible link between excess iron and an increased risk of cancer in animals and humans, particularly colon cancer.23 IP6 has been shown to interfere with iron absorption and reverse iron-dependent augmentation of colorectal tumorigenesis. IP6 also suppresses iron-catalyzed oxygen generation, and almost totally inhibits iron-catalyzed lipid peroxidation.24-25
A concern in this regard, of course, is the possibility that IP6 may deplete the body's mineral stores. In numerous studies, researchers have noted no significant differences in the level of serum or bone minerals in rats, even after lengthy treatment with IP6 and inositol.26
AbulKalam Shamsuddin, MD, PhD, has extensively studied IP6. In a 1997 Life Sciences' article, Shamsuddin stated that "Certainly, its [IP6's] hypothetical harm connected to chelation is far less than that of other compounds of similar usage (eg. cancer chemotherapeutic and chemopreventive agents) and are far outweighed by the plethora of benefits."
The questions that arise in regard to IP6's ability to chelate minerals suggests that other anticancer actions are at play. These actions include:
· Boosting natural defense mechanisms. Natural killer (NK) cells defend the body against tumor initiation. Studies have shown that mice with carcinogen-induced tumors, when treated with IP6, demonstrate augmented NK activity over the untreated controls.27
· Inhibiting carcinogenesis through the "lower IPs." Scientists believe that IP6's actions may be mediated through lower forms of the molecule. One study by Shamsuddin showed that after IP6 treatment of K-562 human erythroleukemia cells, there was a 41% increase in intracellular IP3 and a 26% decrease in IP2. This alteration in the cellular inositol phosphate pool may indicate that the evolution from IP6 to lower forms of the molecule is a crucial step in the inhibition of carcinogenesis.28
· Blocking PI-3 Kinase. PI-3 Kinase is an enzyme necessary for tumor promotion; a normal cell requires PI-3 Kinase to become cancerous. Researchers have found that IP6 is a profound inhibitor of PI-3 kinase.29-30
· Altering cellular communication necessary for tumor growth. Proteins called fibroblast growth factors (FGF) initiate conversations between cells. Each FGF possesses a transmitter and receiver. As these cellular conversations occur, sugar molecules called heparan sulfates intercede to modulate the messages, flowing back and forth via the FGF system. It is through this process that a very specific type of heparan sulfate works in different tissues to maintain proper function and control cell division. Fibroblast growth factors have been implicated in tumor cell growth, as certain cancer cell lines have been shown to express FGF binding sites. IP6 mimics one specific part of the long heparan sulfate chain, thereby interfering with the functioning of the entire heparan sulfate molecule, suppressing DNA synthesis and cell division induced by FGFs.31-32
· Stimulating the p53 gene. If the tumor suppressor gene p53 is not functioning, cancer cells become more resistant to chemotherapeutic agents. IP6 has been shown to up-regulate the expression of p53.33
In 1988, Shamsuddin reported in the journal Carcinogenesis the stunning effect IP6 had on large intestinal cancer in rats. Researchers fed 1% sodium inositol hexaphosphate (Na-IP6) to one group of animals one week prior to inducing cancer, and to another group two weeks after the last dose of a carcinogen was administered. Rats who took the IP6-laced drinking water prior to carcinogen treatment exhibited a 35% decrease in large intestinal cancer compared to the control carcinogen group. The group fed IP6 after receiving the carcinogen showed a similar reduction.34
In 1989, Shamsuddin and colleagues fed rats 2% IP6 in drinking water five months after induction of carcinogenesis. Compared to untreated rats, animals on IP6 had 27% fewer tumors and the tumors were approximately two-thirds smaller in size. This suggests that IP6 may be important in both the treatment and prevention of cancer.35
Phytic acid (IP6) was also effective at reducing the incidence of colon tumors in conjunction with a high risk, high fat diet. The incidence of colon tumors in carcinogen-treated rats plummeted from up to 70% in the control groups to 30% in the groups fed a high risk diet (HRD) plus phytic acid.36
Pretlow and colleagues (1994) demonstrated that IP6 is an even more powerful chemopreventive agent than selenium in halting the development of colon carcinogenesis.37
Diets high in fat and iron have been linked to an increased risk of mammary cancer. In clinical studies, IP6 has mitigated the dangerous consequences of a high fat diet. Dietary administration of phytic acid (2%) in conjunction with carcinogens and a HRD led to a significant reduction in the incidence of mammary tumors in rats compared to those consuming only the HRD. Twenty-one weeks after administration of the carcinogens and the HRD, the incidence of mammary tumors in the HRD plus phytic acid group was reduced by up to 50%.38-39
IP6 has been shown to inhibit carcinogenesis in all types of mammary cancer cells—those that require estrogen for growth and those whose growth is independent of the female sex hormone. It accomplishes this by inhibiting DNA synthesis and cell growth, and inducing differentiation of the cancer cell lines.40-42
In vivo and in vitro studies have shown that IP6 has a protective effect against lung, liver, prostate and skin cancers.
· Prostate Cancer - Shamsuddin noticed a significant dose-dependent growth inhibition in human prostate cancer cells in vitro. As early as three hours after treatment and continuing up to 48 hours, IP6 suppressed DNA synthesis in prostate cancer cells.43
· Hepatocellular Carcinoma - Patients suffering from Hepatocellular carcinoma (HCC), a common liver cancer, usually have an extremely poor prognosis. Studies indicate that IP6 may be an important treatment for this disease. In the first of two experiments, Shamsuddin and colleagues compared the in vitro effects of IP6 on HepG2, a human liver cancer cell line. Compared to other cancer cell lines, HepG2 cells were extremely sensitive to IP6, experiencing a dose-dependent, 50% inhibition of cell growth. IP6 also weakened HepG2's ability to form colonies. The sequel to the experiment demonstrated that IP6 can regress pre-existing human liver cancer cells transplanted in mice back to their normal, non-cancerous state. In addition, the tumor weight in IP6-treated mice was 86% to 1180% less than that in control mice.44-45
· Lung Cancer and Asbestos-Induced Fibrosis - Scientists have also received positive results with IP6 in regards to lung cancer and asbestos-induced fibrosis and carcinoma. Studies have shown that fibrosarcoma cells in mice treated with IP6 resulted in a significant inhibition of tumor and size as well as improvement of survival over the untreated controls. Similar treatment with IP6 of mice with experimental lung metastasis resulted in a significant reduction in the number of metastatic lung colonies. Due to its antioxidant properties and its ability to chelate iron, IP6 diminishes the asbestos-induced oxidative damage that results in inflammation and fibrosis in the lungs of exposed animals, from six to 30-fold less than in control groups.46-47
· Skin Cancer - In a pilot study of mouse skin carcinogenesis, Zarkovic and colleagues reported that IP6 prevented skin papillomas when given during cancer initiation. After initiation however, IP6 exerted little effect. In regards to skin cancer, scientists are calling for more studies to determine IP6's effectiveness in patients who have already been diagnosed with the disease.48
· Rhabdomyosarcoma - IP6 has suppressed the growth of rhabdomyosarcoma, the most common soft tissue sarcoma in children. Cell line growth was reduced by 50% in vitro in a dose-dependent fashion. After two weeks, IP6 treated mice experienced 25-fold smaller tumors and a 49-fold reduction in tumor size after five weeks.49
Kidney Stones, Platelet Aggregation, Heart
Attacks and HIV
A multifaceted nutrient, IP6 has been shown to benefit a number of other conditions. Researchers at the Harvard Medical School and Massachusetts General Hospital in Boston successfully used pure Na-InsP6 to treat idiopathic hypercalciuria, which is associated with a high incidence of kidney stones.50
Other research points to IP6's usefulness in preventing platelet aggregation—a prime cause of heart attacks and strokes. In one study, IP6 inhibited platelet aggregation by 45% in an in vivo animal model. An in vitro study by the same researchers, stickiness was induced in human whole blood taken from healthy volunteers. IP6 reduced clotting by 50%, or eliminated it altogether.51
Other research points to IP6's role in controlling the damage inflicted upon the myocardium (heart muscle) during heart attacks. After a heart attack, doctors reperfuse (fill) the heart area with oxygenated blood. This poses its own set of risks, because the oxygen can churn out free radicals, damaging the blood vessels and heart muscle. Researchers successfully used IP6 to protect the heart muscle from superoxide damage during reperfusion.52-53
As more studies unfold, additional properties of IP6 have been revealed. Otake and colleagues demonstrated that IP6 inhibited the cell destruction induced by HIV as well as the HIV specific antigen expression. IP6's ability to boost natural killer cells could have future implications for AIDS sufferers.54
In his book, IP6: Nature's Revolutionary Cancer Fighter, Shamsuddin, calls IP6 combined with inositol, "an anticancer cocktail." IP6 combined with inositol exerts an even more powerful suppression of cell proliferation and colorectal cancer than with either agent alone. This potent "cocktail" has also been used to suppress carcinogenesis in mammary and metastatic tumor models. Other studies point to the synergistic effect of green tea and phytic acid. When scientists combined these two substances, they had a significant impact on precancerous lesions in rats.55
Dietary IP6 Less Effective
When administered in the diet, IP6 binds with proteins, forming insoluble complexes that are less readily metabolized and absorbed. Because IP6 is particularly abundant in the bran part of certain mature seeds such as wheat, one group of scientists investigated whether a high-fiber bran diet containing high IP6 inhibits rat mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA). Rats were fed a diet containing, 5%, 10% or 20% Kelloggs' All Bran; another group received 0.4% IP6 in drinking water equivalent to that in 20% bran. The fifth group served as the control. After 29 weeks, compared with the carcinogen control, tumor incidence was reduced by 16.7%, 14.6% and 11.4% in rats fed 5%, 10% and 20% bran, respectively, not an insignificant amount. However, rats fed 0.4% IP6 in drinking water had a whopping 33.5% reduction in tumor incidence and nearly 50% fewer tumors.
Researchers stated: "Thus, IP6, an active substance responsible for cereal's beneficial anticancer effect, is clearly more effective than 20% bran in the diet. ...Intake of IP6 may be a more pragmatic approach than gorging enormous quantities of fiber for cancer prophylaxis."56-57
Safety of IP6
The majority of clinical studies have confirmed the safety of IP6. Shamsuddin and colleagues witnessed no adverse effects on body weight, serum mineral content or any pathological changes of consequence after administering IP6 to F344 or female Sprague-Dawley rats for 40 weeks. The safety of IP6 has also been confirmed in human studies. Researchers at Harvard Medical School and Massachusetts General Hospital administered pure Na-InsP6 orally to 35 patients at a dose of 8.8 grams (!) per day in divided doses for an average of 24 months. The patients showed no signs of any toxic reactions. Furthermore, researchers have noted that the cell division rate of healthy animals receiving IP6 shows no deviation from the normal.58-60
There is admittedly a dearth of human clinical studies confirming the potential cancer-fighting effects of IP6. Nevertheless, there are certainly ample theoretical reasons why it should be effective, as well as a number of in vitro and in vivo studies that document its ability to normalize cancer cells and reduce tumors in experimental animals. Furthermore, there are animal and human studies confirming the absolute safety of IP6. Consequently, in view of the evidence for potentially great benefit and total lack of toxicity, rather than wait years for further human double-blind placebo controlled studies to be performed, we believe that IP6 should be considered an absolutely essential element in any broad spectrum nutritional cancer preventive or therapeutic program.
1. Shamsuddin AM, Ullah A, Chakravathy A. Inositol and inositol hexaphosphate suppresses cell proliferation and tumor formation in CD-1 mice. Carcinogenesis. 1989; 10(8):1461-1463.
2. Shamsuddin AM, Baten A, Lalwani ND. Effects of inositol hexaphosphate on growth and differentiation in K-562 erythroleukemia cell line. Cancer Lett. 1992; 64:195-202.
3. Shamsuddin AM, Yang GY. Inositol hexaphosphate inhibits growth and induces differentiation of PC-3 human prostate cancer cells. Carcinogenesis. 1995; 16(8):1975-1979.
4. Doll R, Peto R. The Causes of Cancer. New York, NY: Oxford University Press. 1981.
5. American Cancer Society. 1994. Cancer Facts and Figures. American Cancer Society, New York.
6. Adlercreutz H. Western diet and Western disease: some hormonal and biochemical mechanisms and associations. Scand J Clin Lab Invest. 1990; 201 (Suppl.), 3-23.
7. Pretlow TP, Hudson L, O'Riordan MA, Pretlow TG. Adv in Exper Med Biol. 1995; 375:204.
8. Irving D, Drasar BS. Fibre and Cancer of the Colon. Br J Cancer. 1973; 28:462-463.
9. Alabaster O, Tang Z, Shivapurkar N. Dietary fiber and the chemopreventive modelation of colon carcinogenesis. Mutat Res. 1996; 350(1):185-97.
10. Englyst HN, Bingham SA, Wiggins HS, Southgate DAT, Seppanen R, et al. Nonstarch Polysaccharide Consumption in Four Scandinavian Populations. Nutr Cancer. 1982; 4:50-60.
11. Graf E, Eaton JW. Dietary Suppression of Colonic Cancer: Fiber or Phytate? Cancer. 1985. 56:717-18.
12. Szwergold BS, Graham RA, Brown TR. Observation of inositol pentakis- and hexakis-phosphates in mammalian tissues by 31P NMR. Biochem Biophys Res Commun. 1987; 264:874-81.
13. Huisamen B, Lochner A. Inositolpolyphosphates and their binding proteins—a short review. Mol Cell Biochem. 1996; 157(1-2):229-32.
14. Graf E and Empson KL. Phytic acid: a natural antioxidant. J Biol Chem. 1987; 262:11647-50.
15. Huang C, Ma W, Hecht SS, Dong Z. Inositol Hexaphosphate Inhibits Cell Transformation and Activator Protein 1 Activation by Targeting Phosphatidylinositol-3' Kinase. Cancer Research. 1997; 57:2873-78.
16. Vallejo M, Jackson T, Lightman S, Hanley MR. Occurence and extracellular actions of inositol pentakis- and hexakisphosphate in mammalian brain. Nature (Lond.). 1987; 330:656-58.
17. Yang GY, Shamsuddin AM. Anticancer Res. 1995; 15:2479-88.
18. Sakamoto K, Venkatraman G, Shamsuddin AM. Carcinogenesis. 1993; 14:1815-19.
19. Shamsuddin AM, Yang GY. Carcinogenesis. 1995; 16:1975-79.
20. Shamsuddin AM, Yang GY, Vucenik I. Novel Anti-Cancer Functions of IP6: Growth Inhibition and Differentiation of Human Mammary Cancer Cell Lines In Vitro. Anticancer Res. 1996; 16:3287-92.
in Cancer Research
Studies of Reishi in cancer research have been largely conducted in Japan, where Reishi was scientifically proven to have an anti-tumor effect. This research has continued in Korea, Japan, and China.
An example of Reishi's cancer-fighting potential occurred in the summer of 1986. A 39-year old Japanese woman approached Dr. Fukumi Morishige, M.D., Ph.D, a renowned Japanese surgeon and a member of the Linus Pauling Institute of Science and Medicine, for help in treating her lung cancer. It was a complicated case, and she had been refused an operation by several hospitals. Hopeless, she returned home where she found her husband had collected Reishi in the forests. He boiled the mushroom and gave it to her to drink as a tea.
While this was going on, she begged Dr. Morishige to do something for her cancer, regardless of its very advanced stage. From what was evident six months earlier, Morishige was surprised when he found no increase in swelling. Then he looked at her X-rays. Something wasn't right: her tumor showed as only a trace on the X-ray. When she told him she had been drinking Reishi tea, Morishige operated with great curiosity. He was "astonished" to find only scar tissue, and although cancerous cells remained, they were now benign.
That was the impetus for Dr. Morishige to begin his studies of Reishi as a treatment for cancer especially cases given up as hopeless. Dr. Morishige now believes that Reishi is also an effective cancer preventive. The active anti-cancer constituents in Reishi are called Beta-D-glucan. Beta-D-glucan is a polysaccharide--basically a huge sugar molecule made up of many little sugar molecules chained together bound to amino acids. These intricate sugars stimulate or modulate the immune system by activating immune cells such as macrophage and helper T-cells, as well as increase the immunoglobin levels (immunoglobins are specific types of antibodies) to produce a heightened response to foreign cells, whether bacteria, viruses, or tumor cells.
One interesting and important finding by Dr. Morishige was that the effectiveness of Reishi could be increased by combining it with high doses of vitamin C. Polysaccharides are huge molecules absorbed by the body with difficulty. Vitamin C helps to break down these huge molecules to much smaller molecules called oligoglucan, which can be easily absorbed. Vitamin C thus increases the bioavailability of Reishi, and therefore, synergistically increases Reishi's immune-stimulating and anti-cancer effects.
by James South, MA
Heart disease and cancer are the two main causes of death in America and Europe. These diseases kill about 2/3 of all adults. The "fatty/cholesterol plaque" that can occlude arteries is called atheroma. The gradual development of atheroma in heart arteries is referred to as coronary atherogenesis; and a chief culprit in the process of atherogenesis is cholesterol/saturated fat. High levels of LDL cholesterol and/or low HDL cholesterol are generally believed to be the chief culprits in atherogenesis.
Thrombi vs. Atheroma
However, a mass of evidence dating back 40 years clearly points to another cause of heart attacks that may be just as important as atheroma/atherogenesis as the cause of our 20th century epidemic of heart attacks. In fact, Keeley and Higginson in 1957 suggested that thrombi [abnormal blood clots] rather than atheroma may be the major cause of myocardial infarctions (MIs). Thomas and his colleagues, like Keeley and Higginson, said that it was high time more concern be shown to the danger of thrombi. In 1980, Sinclair stated that thrombosis—not atheroma—is the major causal factor in MI.1
Kinsella, et al, also highlight the importance of platelet aggregation/thrombogenesis in MI deaths: "...the antioxidative agents in plant foods and wine may also be very effective in reducing thrombosis and blockage of narrowed arteries, which is a fatal event in more than 90% of deaths from CHD [coronary heart disease]... Thus, the partially occluded [by atheroma] artery is easily blocked by thrombi formed mostly from aggregated blood cells that rapidly aggregate and clump in response to specific stimuli."13
In a classic 1992 article about the "French paradox for heart disease," Renaud and de Lorgeril present evidence that dietary fat and blood cholesterol may not be primary MI villains, at least among the French. They note that the annual mortality rate per 100,000 population from coronary heart disease (CHD) is 78 in Toulouse, France, and 105 in Lille, France (for men), compared to 182 in Stanford, USA, 348 in Belfast, UK, and 380 in Glasgow, UK. Yet the saturated fat intake is about the same for all these groups—15% of total calories. The mean serum cholesterol is notably lower for men in Stanford (209 mg) than in France (230 in Toulouse, 252 in Lille), while Belfast (232) and Glasgow (244) levels are similar to France. Nevertheless, all three have higher MI mortality rates than France.
Renaud and de Lorgeril report that "...in the 17 countries that report wine consumption, wine is the only foodstuff in addition to dairy fat that correlates significantly with mortality...wine has a...protective effect."2 Renaud and de Lorgeril then present evidence that it is not through inhibitory effects on atherosclerotic lesions (atheroma) that wine provides MI protection, but rather through a decrease in the tendency of platelets to aggregate and ‘plug up' heart arteries. They note "...we have compared farmers from Var, Southern France (low in CHD mortality), with farmers from south-west Scotland for [platelet aggregation tendencies]. Platelet aggregation was strikingly lower in Var. Consumption of alcohol was greatest in Var (45g per day vs. 20g per day in Scotland), mostly in the form of wine."2
Lest anyone derive from this the moral that alcohol, per se, is beneficial for heart health, several points should be noted. As Goldberg, et al, state, "...ethanol or a metabolite impairs the platelet function as a consequence of...platelet injury."3
The Red Wine Connection
Goldberg, et al, reported that the lowest risk of CHD mortality was among those who drank wine compared with those preferring [other alcoholic] beverages, especially at higher rates of consumption.3 These authors also reported that when "16 healthy subjects were given [pure] alcohol, white wine and red wine [for 15 days for each beverage], alcohol enhanced [i.e. increased]...platelet aggregation...Red wine led to a fall in ADP-induced [platelet] aggregation and increased HDL-cholesterol, clearly the most favorable response to the three beverages tested."3 Klurfield and Kritchevsky reported that "Rabbits were fed an atherogenic diet together with water (controls), or one of five different beverages containing equal amounts of ethanol. After 3 months, all the control rabbits had developed atherosclerotic lesions in the coronary arteries. The alcoholic beverages, except beer, reduced the incidence of such lesions, but the most dramatic reduction (to 40% of controls) occurred in the rabbits receiving red wine."3
The above is just a sampling of the evidence that it is primarily red wine, not spirits or beer, that is ‘heart-friendly.' Yet even red wine contains alcohol, and alcohol, especially through its chief metabolite, acetaldehyde, is a powerful and broad-acting metabolic toxin, with liver damage being just the ‘tip of the iceberg' of alcohol's destructive side.4
Thus, it became clear by the early 1990's that something relatively unique to red wine provided significant heart protection. Consequently, nutritional scientists began searching to find the ‘active ingredient(s).'
In a 1995 article, researcher David Goldberg rhetorically asked "What on earth has the color of the wine got to do with it all? A great deal, it seems. The only consistent difference between the red and white wines is that the red contains more phenolic compounds. Among these phenols, the major difference is in the flavonoids...[including] compounds such as quercetin (QRC), rutin, catechin and epicatechin..."5 Goldberg points out that ‘flavonoids' have been demonstrated to have powerful biological effects, including the ability to inhibit eicosanoid synthesis and pathological platelet aggregation, as well as the ability to inhibit cancer growth and development. Goldberg also notes these red wine-phenolics are individually and collectively 10 to 20 times more potent than vitamin E in protecting low-density lipoproteins (LDL) against oxidation (oxidized LDL is now considered to be a powerful initiating mechanism of atherogenesis). Yet Goldberg also points out that people who eat a decent amount of fruits and vegetables will already ingest a fairly healthy dose of flavonoids, so ‘why the fuss about red wine?' (Indeed, the Zutphen Elderly study showed that even the modest amount of flavonoids found in tea, onions and apples, seemed to provide significant protection against death from MI among elderly men consuming these 3 foods, compared to those not consuming them.6
Goldberg then asked the rhetorical question "Does [red] wine contain a biological component that is present only in limited amounts in a typical diet? Indeed, it does: resveratrol (RSV). This trihydroxystilbene is synthesized by grapes, being present in the canes, leaves and the skins of the berries. Because these are present during the fermentation of red wines, but not white wines, only the former contain significant amounts of resveratrol in the finished product."5
The resveratrol story does not begin with its (recent) discovery in wine. It actually started in the early 1980's among Japanese scientific researchers. Reporting in 1982, Arichi, et al, noted that the dried roots of Polygonum cuspidatum have been used in traditional Japanese and Chinese medicine in a product called ‘Kojo-kon.' Kojo-kon was used to treat a wide range of afflictions, including fungal diseases, various skin inflammations, and diseases of the heart, liver and blood vessels. Resveratrol and its glycoside ‘polydatin' have been shown to be the primary active ingredients of Kojo-kon.7
In 1985, Kimura, et al, discovered the key to resveratrol's metabolic activity. Working with rat leukocytes (white blood cells), they showed that resveratrol possesses a powerful ability to inhibit eicosanoid production.
In 1995, Pace-Asciak, et al, reported a dose-dependent inhibition by trans-resveratrol of the aggregation of platelets prepared from healthy human subjects. The IC50 concentrations for resveratrol were approximately 100 micromoles, while ethanol required 1,000 times higher concentrations to achieve the same effect. The standard antioxidants BHT and vitamin E were ineffective at inhibiting platelet aggregation, as were the major wine phenolics catechin and epicatechin.10
Pace-Asciak, et al, also found that trans-resveratrol strongly inhibited the COX-catalyzed thromboxane synthesis by platelets, with approximately 60% inhibition at 10 micromoles resveratrol. None of the other wine phenolics or antioxidants tested had any major effect at that concentration. Only resveratrol—of the other phenolics and antioxidants tested exerted modest LOX inhibition at higher levels.
Platelet LOX activity generates hepoxillins from arachidonic acid (AA), which induce vascular permeability and neutrophil activity, two partial causes of atherogenesis.8,10 As Soleas, et al, note, "...resveratrol at micromolar concentrations is able to inhibit thromboxane A2 production."9 In 1997, Soleas, et al, reported that "...by applying information obtained from dose-response curves, the [platelet] antiaggregatory effect of de-alcoholized red wines could be computed as approximately that expected from its concentrations of resveratrol...."11
Blood Vessel Biology
To more fully grasp the importance of eicosanoids in platelet aggregation, it is necessary to understand a simple fact about blood vessel biology. Healthy, smooth, intact blood vessel linings (the endothelium, a layer only one cell thick) "...synthesize and secrete prostacyclin [PGI2], a strong vasodilator and the most potent inhibitor of platelet aggregation known."13 "...the platelet thromboxane pathway is activated markedly in acute coronary syndromes...PGI2...contributes to the non-thrombogenic properties of the endothelium...PGI2 and TXA2 [thromboxane A2] represent biologically opposite poles of a mechanism for regulating platelet-vessel wall interaction and the formation of hemostatic plugs and intra-arterial thrombi."8
In other words, PGI2 prevents clots from plugging up heart arteries, keeps the arteries dilated (wide open), and promotes healthy endothelial lining. TXA2, however, promotes pathological clotting, constricts arteries, and can damage the blood vessel endothelial lining - i.e. promote atheroma.8 PGI2 is routinely made by healthy endothelial cells from AA, and then secreted into the bloodstream. Prostacyclin synthase (PS) is the enzyme that transforms AA into PGI2.
Free Radicals and Antioxidants
What impairs the activity of PS? Various free radicals and oxidants, especially lipid peroxides and hydroperoxides—these are, essentially, ‘rancid' fats.12,16 Kinsella, et al, state that the prevailing hydroperoxide ‘tone' or concentration is a result of the balance of pro-oxidants (e.g. free copper or iron ions, cigarette smoke), antioxidants and oxidative substrates (i.e. the fatty acids in the blood), and that this balance influences the propensity toward oxidation/ free radical production.13
Thus, in order to maximize production of heart-friendly PGI2, it is necessary to minimize the ‘prevailing hydroperoxide tone' in the blood, since high hydroperoxide tone = low PGI2 synthase activity = low PGI2. (It also helps PGI2 production if one minimizes or eliminates fried fats from the diet, too—these provide rich sources of hydroperoxides/peroxides.) "Antioxidants inhibit lipid peroxidation by reducing general [hydroperoxide] tone...The polyphenolics [including RSV and QRC], commonly found in wine, are potent antioxidants...De Whalley, et al (1990), reported that flavonoids act by protecting (and perhaps regenerating) the primary antioxidant, tocopherol [vitamin E], by direct antioxidant effects, and by scavenging free radicals and peroxy radicals."13 Frankel, et al, reported both RSV and QRC to be more powerful antioxidants than vitamin E in protecting human LDL against copper-catalyzed oxidation.14
In 1994, B. Stavric wrote that "It appears that a number of the biological effects of...flavonoids may be explained by their antioxidative activity and ability to scavenge free radicals."15 It also turns out to be very important to minimize free radical/lipid peroxide production in order to minimize pathological platelet aggregation due to TXA2 excess.
Thus, "the synthesis of these compounds [TXA2 and PGH2] by cyclo-oxygenase is enhanced by lipid hydroperoxides."13 "Free radical production is intrinsically linked with the enzymatic generation of prostaglandins, thromboxanes and leukotrienes from [AA]...Lipid-derived hydroperoxides (HPETE's) are obligatory intermediates in the generation of prostaglandin/thromboxanes... from AA.... Bryant, et al, reported that GP [glutathione peroxidase] reduces the hydroperoxide compound 12-HPETE derived from AA, to its [relatively harmless] derivative 12-HETE.... Any impairment of GP (by lack of availability of [selenium]...) may lead to abnormal accumulation of the HPETE peroxides, which are potent inhibitors of the prostacyclin synthetase."16
Conclusion For Blood
Thus, a combination of resveratrol and other bioflavonoids, vitamin E, vitamin C, and the trace mineral selenium may be expected to have a highly synergistic effect in reducing pathological platelet aggregation (thrombogenesis), maximizing PGI2/minimizing TXA2 (thus dilating arteries for healthy blood flow as well as opposing platelet aggregation) and minimizing free radical damage/disruption to blood vessel linings (i.e. preventing/minimizing atherogenesis).
Resveratrol may also have a similarly beneficial effect in preventing cancer, or even aiding in its cure. Jang, et al (1997) reported the results of a series of biochemical, cell culture, and animal studies with RSV in the prestigious journal Science. They reported that "Resveratrol inhibits cellular events associated with tumor initiation, promotion and progression."17 In other words, resveratrol is able to block all three mechanisms of cancer formation!
These authors also wrote that "...we studied tumorigenesis in the two-stage mouse skin cancer model in which DMBA was used as initiator and TPA as promoter. During an 18-week study mice treated with DMBA-plus TPA developed an average of two tumors per mouse with 40% tumor incidence. Application of 1, 5, 10 or 25 [micromoles] of resveratrol together with TPA twice a week for 18 weeks reduced the number of skin tumors per mouse by 68, 81, 76 or 98% respectively, and the percentage of mice with tumors was lowered by 50, 63, 63 or 88%, respectively. No overt signs of resveratrol-induced toxicity were observed...."17 These authors also noted the importance and potency of RSV's anti-COX activity and antioxidant/anti mutagenic activity in preventing tumor promotion and initiation.
The Cancer, Blood and Antioxidant
In his textbook Cancer & Natural Medicine, J. Boik reports the importance of platelet aggregation and eicosanoid issues in cancer. Thus he writes: "The importance of platelet aggregation in cancer metastasis is more widely accepted... Activated platelets are sticky and may enhance the adhesion of tumor cells to the endothelial lining. Platelet-secreted factors...may stimulate the growth of tumor cells and contribute to their survival within the blood circulation. Experimental studies have shown that migrating cells from some cancers induce platelet aggregation by modifying the eicosanoid balance...Tumors promote platelet aggregation by stimulating the production of PGI2...Tumors synthesize eicosanoids through ...the COX pathway...."19 Given the prior discussion in this article of resveratrol as premier COX-inhibitor, and as an excellent anti-platelet aggregator, its potential anti-cancer benefit should be evident.
Garrison and Somer state that "Several studies report that vitamin E reduces tumor growth and exerts an anti-cancer effect in both the initiation and promotion stages because of its antioxidant and immuno-enhancing actions... vitamin E appears more effective in conjunction with other nutrients, such as selenium and ascorbic acid, than by itself in the prevention of tumor growth."18
Some question has been raised over the oral absorbability of resveratrol, but recent results clearly demonstrate its excellent absorption. Soleas, et al, comment that "...the difference in thrombin-induced platelet aggregation between the commercial and resveratrol-enriched grape juices argues in favor of the absorption of this compound in biologically active concentrations by human subjects..."9
Uses and Doses
A simple yet elegant and potent anti-heart attack/anti-cancer program may thus be constructed from synergistic nutrients: Resveratrol, vitamin E, vitamin C and selenium. Recommended dosages: 1-10 mg trans-Resveratrol, 3 times daily. 100-400 IU d-alpha tocopherol or d-alpha tocopheryl succinate (vitamin E), once daily with a fat-containing meal. 250-1000 mg ascorbate (vitamin C), 4 times daily. 100 mcg once daily, or 50-100 mcg twice daily, selenium as l-selenomethionine and/or sodium selenate.
Caution: Anyone who suffers from platelet deficiency or blood-clotting difficulties should use this program only under medical supervision, if at all. Similarly, anyone taking medical blood-thinning drugs (e.g. aspirin, coumadin) should use this program only under medical supervision, if at all.
1. W. Martin (1984) ‘The combined role of atheroma, cholesterol, platelets, the endothelium and fibrin in heart attacks and strokes' Med Hypoth 15, 305-22.
2. S. Renaud, M. de Lorgeril (1992) ‘Wine, alcohol, platelets, and the French paradox for coronary heart disease' Lancet 339, 1523-26.
3. D.M. Goldberg et al (1995) ‘Beyond alcohol: Beverage consumption and cardiovascular mortality' Clin Chim Acta 237, 155-87.
4. J. South (1997) ‘Acetaldehyde: A common and potent neurotoxin' VRP Nutr News 11, 1-2, 9-11.
5. D.M. Goldberg (1995) ‘Does wine work?' Clin Chem 41, 14-16.
6. M.G. Hertog et al (1993) ‘Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly study' Lancet 342, 1007-11.
7. H. Arichi et al (1982) ‘Effects of stilbene components of the roots of Polygonum cuspidatum... on lipid metabolism' Chem Pharm Bull 30, 1766-70.