Cancer

(See Table 7 for a summary of the following cancer related studies.)


Review of Recent Cancer Studies

Cancer is characterized by unlimited growth and proliferation of otherwise healthy cells. Normally, genetic signals in cells regulate reproduction and growth. Some signals tell the cell to stop growing and reproducing, while others induce further growth and reproduction. Excessive free radicals may damage these signals, and the cell may become cancerous, unable to stop growing and reproducing. Moreover, cancerous cells are a source of free radicals, potentially causing more damage. Unchecked, the wild proliferation of cells starves the rest of the body of nutrients, ultimately killing the person. Ironically, conventional cancer therapies utilize drugs and/or radiation to induce free radicals which destroy the cancerous cells. Unfortunately, the treatment often indiscriminately kills healthy cells, too, often leading to serious side effects. Current efforts are underway to more precisely target these therapies to kill just the diseased cells.

Many researchers believe antioxidant nutrition may play an important role in preventing cancer. By protecting the cells from excess free radical damage, antioxidants may spare critical genetic signals from oxidative damage which would have otherwise resulted in cancerous changes.

In this review paper, the results of 7 clinical trials, 16 population studies, and 36 case-control studies from 1980 to 1996 on antioxidant supplements and cancer were analyzed. The following observations could be made:

- Overall, there is evidence modestly supporting the protective effects of antioxidant supplements against several kinds of cancers.

- Vitamin E was found to protect against prostate, stomach, and colon cancer.

- Vitamin C was found to protect against bladder cancer.

- Vitamin A was found to protect against breast cancer.

- Beta-carotene was found to protect against stomach cancer.

- Selenium was found to protect against total, lung, and prostate cancers.

While the results are generally encouraging, much more clinical research needs to be done to better understand the relationship between antioxidant supplements and cancer. Many current studies find no obvious benefits, and some even suggest adverse effects. There is evidence and rationale to believe excessive amounts of antioxidants become pro-oxidant, that is, actually causes free radical activity. If the protective effect is real, the optimal dosage and frequency of supplementation needs to be carefully determined by future, well-designed studies.

Patterson, R., White, E., Kristal, A., Neuhouser, M., Potter, J. Vitamin Supplements and Cancer Risk: The Epidemiologic Evidence. Cancer Causes and Control. Vol. 8, pp.786-802, 1997.

Protects Against Certain Cancers

In this study from the Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland, samples of blood from 25,802 volunteers who gave blood to a serum bank were frozen and stored. The subjects were mostly between the ages of 35 to 64, better educated, and females outnumbered the males. In the following years, 436 subjects developed cancer (colon, rectum, pancreas, lung, melanoma, basal cell of skin, breast, prostate, and bladder), identified through the regional cancer registry. For each cancer case, two healthy controls were matched according to age, race, sex, month blood was donated, and time between blood drawing and the previous meal. The original, frozen blood samples from the 1,201 subjects were then thawed and tested for vitamin E and various carotenoid levels.

Analysis of the resulting data showed higher serum vitamin E levels protected against lung cancer. Also, serum beta-carotene levels provided strong protection against lung cancer, and weaker protection against melanoma and bladder cancer. Low levels of lycopene were also strongly associated with pancreatic cancer and less strongly associated with bladder and rectal cancer.

Comstock, G., Helzlsouer, K., Bush, T. Prediagnostic Serum Levels of Carotenoids and Vitamin E as Related to Subsequent Cancer in Washington County, Maryland. American Journal of Clinical Nutrition. Vol. 53(suppl), pp.260-4, 1991.

Cancer Risk

In this study from the University of Tampere, Finland, 36,265 adults provided blood samples which were frozen and stored. The age range of the subjects was 15 to 99, and they came from 25 population groups in various parts of Finland. After around 8 years, 766 subjects developed various forms of cancer. The levels of vitamin E and other antioxidants were found from the original blood samples of these subjects along with those of 1,419 non-cancer control subjects, matched for age, sex, and duration of sample storage.

The mean serum vitamin E concentration of cancer patients was on average 3% lower than those of healthy controls. The difference held statistical significance. Men in the lowest 60% and women in the lowest 20% of vitamin E levels had a 150% greater risk of developing cancer compared with those who had higher levels. Among men, non-smokers with low vitamin E levels had twice the cancer risk as other non-smoking men. Smoking men did not show a similar association. Among women, those with both low serum vitamin E and selenium levels had three times higher risk of hormone-related cancers.

The authors point out the nature of the study could not distinguish whether the lower levels of vitamin E in cancer patients were the cause or result of the disease. Taken with the findings of other studies, a causal relationship is possible, but requires further research to clarify.

Knekt, P., Aromaa, A., Maatela, J., Vitamin E and Cancer Prevention. American Journal of Clinical Nutrition. Vol. 53(suppl), pp.283S-6S, 1991.

Gamma-tocopherol and Subsequent Prostate Cancer

From the Johns Hopkins School of Hygiene and Public Health in Baltimore, Maryland, this epidemiological study suggests that gamma-tocopherol may be more important than alpha-tocopherol and selenium in preventing subsequent prostate cancer. In 1989, nearly 10,500 men over the age of 45 in Washington County, Maryland, gave blood samples which were stored. In the following 8 years, 145 men developed prostate cancer. Of these, 117 men and 233 matched controls had toenail and plasma samples measured for alpha- and gamma-tocopherol, and selenium. Those having the top fifth of alpha-tocopherol concentrations were 35% less likely to develop prostate cancer compared with those in the bottom fifth. For gamma-tocopherol, the risk reduction was even greater: those in the top fifth had a 500% reduction in risk, compared to those in the bottom fifth. The risk reduction of selenium was suggestive, but not nearly as strong as the tocopherols. Moreover, protective associations for high selenium and alpha-tocopherol levels were found only when gamma-tocopherol levels were high.

The authors believe their findings point to the possibility that gamma-tocopherol may be significantly protective against subsequent prostate cancer. They point out that most vitamin E supplements on the market emphasize alpha-tocopherol, and in light of these findings, other forms of vitamin E may provide additional health benefits. In fact, some studies suggest high intake of alpha-tocopherol may diminish gamma-tocopherol concentrations in the plasma and tissues, so supplements having a more balanced blend of different forms of tocopherols may provide certain advantages.

Helzlsouer, K.J., Huang, H.Y., Alberg, et al. Association Between alpha-Tocopherol, gamma-Tocopherol, Selenium, and Subsequent Prostate Cancer. Journal of the National Cancer Institute, Vol. 92, No. 24, 2000.

Vitamin E Succinate Modulates Leukemia Cells

An esterified form of vitamin E, alpha-tocopheryl succinate, has been shown to exhibit anti-cancerous properties in vitro. Vitamin E succinate is not an antioxidant unless the succinate is removed, a process known as de-esterification of the vitamin E, which does occur in the body. Nevertheless, it may have special properties distinct from unesterified vitamin E.

In this study conducted at the University of Texas, Austin, Texas, vitamin E succinate (natural source"RRR-alpha-tocopheryl succinate) at a concentration of 15 micrograms per milliliter was added to a sample of human promyelocytic leukemia cells. The leukemia cells can be induced to mature and proliferate by adding other substances. However, the vitamin E succinate suppressed cell proliferation by 63% after 24 hours and 89% after 48 hours compared to control samples without the vitamin E. Moreover, when vitamin E succinate was removed, the normal proliferation began again, showing the suppression was directly dependent on vitamin E succinate's presence. The treated cells did not show any changes in expression of surface proteins or the way they moved, but did develop changes in structure. Thus, vitamin E succinate may play a role in modifying human promyelocytic leukemia cells and suppressing their proliferation in vitro.

Tuley, J., Sanders, B., Kline, K. RRR-alpha-Tocopheryl Succinate Modulation of Human Promyelocytic Leukemia (HL-60) Cell Proliferation and Differentiation. Nutrition and Cancer. Vol. 18, pp.201-213, 1992.

Vitamin E Succinate and Prostate Cancer Cells

Apoptosis occurs when a cell signals itself to die. When apoptosis begins, the cell stops growing and produces large amounts of enzymes, which ultimately dissolves away the rest of the cell. Normal cells undergo apoptosis at the end of their life, but not cancerous cells, which continue to live and reproduce indefinitely.

In this study also from the University of Texas, Austin, Texas, vitamin E succinate (natural-source"RRR-alpha-tocopheryl succinate) in concentrations of 5, 10, and 20 micrograms per milliliter was used to treat cultures of human prostate cancer cells for 1 to 3 days. Compared to controls, the vitamin E treated cells induced apoptosis in a dose-dependent and time-dependent manner. That is, the higher the concentration and longer treatment of vitamin E succinate, the more cancer cells automatically self-destructed via apoptosis. For example, after 3 days of treatment with 10 micrograms per ml vitamin E succinate, 100% of a certain cancer cell line underwent apoptosis, and 60% of another. Healthy human prostate cells treated with vitamin E succinate appeared resistant to the same effects. The researchers performed other experiments to determine the mechanism involved and suggest vitamin E succinate alters the signaling of a surface receptor (Fas) which induces apoptosis in cancerous cells.

Isreal, K., Yu, W., Sanders, B., Kline, K. Vitamin E Succinate Induces Apoptosis in Human Prostate Cancer Cells: Role for Fas in Vitamin E Succinate-Triggered Apoptosis. Nutrition and Cancer. Vol. 36, pp.90-100, 2000.

Tocotrienols and Human Breast Cancer

In another in-vitro study from the University of Texas, Austin, Texas, tocotrienols were found to significantly induce apoptosis in human breast cancer cells. Two human breast cancer cell cultures (estrogen responsive MCF7 and non- responsive MDA-MB-435) were treated with natural-source tocotrienols (alpha, gamma, and delta), as well as tocopherols (RRR-alpha-tocopheryl succinate, RRR-alpha-tocopheryl acetate, RRR-alpha-tocopherol, RRR-beta-tocopherol, RRR-gamma-tocopherol, and RRR-delta-tocopherol.) The succinate form was used as the control, since it has established anti-cancer properties. The cell cultures were treated with these tocotrienols and tocopherols for up to three days and examined visually for apoptosis. A characteristic quantity, EC50, was thus determined for each compound. (The EC50 is the concentration in micrograms per milliliter of the compound that induces 50% of the cells to undergo apoptosis. The lower the EC50 value, the better the compound is able to induce apoptosis.)

As the control substance, RRR-alpha-tocopherol succinate had an EC50 of around 7. That is, 7 micrograms per milliliter of the succinate effectively induced apoptosis of 50% of the cancer cells. RRR-alpha-tocopherol acetate, RRR-alpha- tocopherol, RRR-beta-tocopherol, and RRR-gamma-tocopherol all had EC50s over 200, making them ineffective as inducers of apoptosis. However, RRR-delta- tocopherol had an EC50 of around 100, making it the only tocopherol that was marginally effective.

The tocotrienols, on the other hand, were very powerful inducers of apoptosis, with EC50s of 7 to 176. In order of effectiveness, delta-tocotrienol is the best, followed by gamma- and alpha- tocotrienols.

The authors conclude that the tocotrienols were found to be potent inducers of apoptosis of estrogen responsive and non-responsive human breast cancer cell lines, but with the exception of delta-tocopherol (and tocopheryl-succinate), the other tocopherols were not. The antitumor properties of tocotrienols are worth further exploration. The authors point out that one important factor which needs to be carefully considered is how tocopherols may lessen or block the anti-cancer properties of tocotrienols. To maximize cancer treatment effectiveness, tocopherols may need to be avoided, while tocotrienols emphasized. However, much research is required to clarify the interrelationships.

Yu, W., Simmons-Menchaca, M., Gapor, A., Sanders, B., Kline, K. Induction of Apoptosis in Human Breast Cancer Cells by Tocopherols and Tocotrienols. Nutrition and Cancer, Vol. 33, Issue 1, pp. 26-32, 1999.

Tocotrienols Inhibit Human Breast Cancer Cell Growth

In this in-vitro study from the Palm Oil Research Institiute of Malaysia, tocotrienol-rich concentrates of palm oil and individual tocotrienol fractions (alpha, gamma, and delta) were found to inhibit the growth of three human breast cancer cell lines, two (MCF7 and ZR-75-1) which are estrogen responsive, and one (MDA-MB- 231) which is not. At low concentrations, the tocotrienols were found to actually stimulate growth of the cancer cells, but at high concentrations, they strongly inhibited growth. Alpha-tocopherol was also tested and found not to have similar inhibitory ability, consistent with the results of other studies. The tocotrienol-rich concentrate was also found to work together with the anti-estrogen drug tamoxifen. Similarly, the individual tocotrienols worked together with estradiol and pure anti-estrogen ICI 164,384 to inhibit growth of one of the estrogen-responsive cell lines. The authors are enthusiastic about their results, which provide additional evidence supporting the potential effectiveness of tocotrienols in treating cancer.

Nesaetnam, K. Dorasamy, S., Darbre, P.D. Tocotrienols Inhibit Growth of ZR-75-1 Breast Cancer Cells. International Journal of Food Science and Nutrition. Vol. 51, Suppl., pp.95-103, 2000.

Breast Cancer Risk

In the 10 year period 1977 to 1987, a total of 7,224 women donated blood to the Columbia Missouri Breast Cancer Serum Bank one or more times. In approximately the next 10 years, 105 confirmed breast cancer cases were diagnosed among the women. For each cancer patient, two women who did not have cancer were matched for age and date of blood collection. Levels of carotenoids, vitamin E, selenium, and vitamin A were measured from their original blood samples and compared. The main findings:

- A increasing serum lycopene concentration decreased risk of breast cancer in all women, and the association was especially significant for those who donated blood at least 2 years before diagnosis.

- Higher lutein and zeaxanthin levels were moderately associated with lower risk.

- Increasing serum beta-cryptoxanthin concentration was associated with decreasing risk, though not significantly.

- No associations could be found for the other carotenes, vitamin E, vitamin A, or selenium.

Dorgan, J., Sowell, A., Swanson, C. et al. Relationships of Serum Carotenoids, Retinol, alpha-Tocopherol, and Selenium with Breast Cancer Risk: Results from a Prospective Study in Columbia, Missouri (United States). Cancer Causes and Control. Vol. 9, pp.89-97, 1998.

Vitamin E Acetate and Mouse Tumor

In this experiment at the Ottawa Regional Cancer Center, Ontario, Canada, mutagenic cells which cause tumors to grow were grafted into mice. Some of the mice were fed vitamin E acetate (natural-source"d-alpha-tocopherol acetate"), an esterified form of vitamin E, in the amount of 2 IU per kg body weight in their food for 3 to 4 weeks, while others who did not receive the vitamin E served as controls. In some experiments, glyceryl trinitrate, a source of the free radical nitric oxide, was also given in the diet. After the trial period, the tumorous cells were removed from the mice and cultured for several days. The main findings:

- Vitamin E reduced the average mutation frequency in one kind of tumor cell by 24.9%.

- Vitamin E reduced the average mutation frequency in another tumor cell line by 68.9% and 84.1% in two separate experiments.

- Vitamin E reduced the levels of a certain free radical in the above two experiments by 75.3% and 75.5%.

- Vitamin E reduced the average mutation frequency of glyceryl trinitrate-induced mutations by 61.4%.

The researchers believe the results of this study suggest vitamin E acted by neutralizing free radicals such as nitric oxide, as well as preventing free-radical inducing immune cells from entering tumors. "In summary, our results suggest that vitamin E may exert antimutagenic/anticancer properties by two distinct mechanisms. Both of these mechanisms should be taken into account in the planning of future clinical trials."

Sandhu, J., Haqqani, A., Birnboim, C. Effect of Dietary Vitamin E on Spontaneous or Nitric Oxide Donor-Induced Mutations in a Mouse Tumor Model. Journal of the National Cancer Institute. Vol. 92, pp.1429-33, 2000.