Folate for the Prevention of Colon Cancer

By Michael F. Roizen, MD

According to food and drug administration daily value Guidelines,1 most of us need folic acid supplements. The typical American diet has 300-400 mcg of vitamin B9, or folate. That’s more than Americans have been getting because the grain supply is now supplemented with 100 mcg of folate per 100 g of grain, yielding approximately 25 mcg in most servings of grain products in the United States. The intent of this fortification was to prevent birth defects, notably spinal cord malformations and nervous system deficits such as spina bifida.2 Still, it’s too little for optimal health in more than 75% of Americans.

Retrospective studies have shown a clear association between homocysteine levels and atherosclerotic disease. Dietary or supplemental folic acid can lower homocysteine levels by 5-6 micromol/L with a daily intake of 400 mcg.3 Recent evidence indicates folic acid supplementation is also beneficial for men who wish to father children as it increases sperm count (by 40% in subfertile men).4

There is now substantial evidence that if we don’t take folate for those reasons, we should take it to prevent colon cancer. We should make sure we and our patients get enough through diet (see Table 1) and supplementation (800 mcg/d) to enjoy the 40% reduction in clinical cases of colorectal cancer that folate affords.

Mechanism of Action

Folate and all its coenzymatic forms have one function in mammalian systems: to mediate the transfer of the carbon methyl units. Two major pathways are served—the production of S-adenosylmethionine and deoxynucleoside triphosphate synthesis. Methyl donation facilitators are necessary for normal synthesis of the pyrimidine thymdylate, and the purines, including cytosine.5-8

Deficiency of uracil and cytosine have been shown in in vitro systems to cause cancer by making DNA more fragile. Such deficiencies also cause cancers by making miscoding accidents more prevalent, inhibiting the P53 tumor-suppressor gene, and promoting growth of already established cancers.

Thus, methyl donor deficiency can cause DNA mutations, promote DNA mutations, and promulgate DNA mutations.5-8 Whether folate deficiency starts a clinical cancer or just promotes the clinical evidence of already formed cancers is important, but we do not know which mechanism is at work in human cancer. All four possible mechanisms (see preceding paragraph) make it biologically plausible that folic acid supplementation may reduce the risk of clinically evident colon cancer.

Clinical Studies

Solid research studies, some published as long ago as 1991, indicate that increasing folate intake can prevent or reduce the risk of colon cancer.9-14 (See Table 2.)

The strongest of these studies is the 1998 publication of the 15-year follow-up of the Nurse’s Health Study.11 In this study, the relative risk for colon cancer in the highest intake group (> 400 mcg/d) was 31% less than that of the lowest intake group (< 200 mcg/d). The longer the exposure to high-folate intake, the greater the risk reduction for colon cancer, reaching a 75% risk reduction after 15 years of high intake compared to the lowest intake.

This prospective cohort study is strong because of the large number (88,756) of nurses about whom data were collected, and because of its adjustment for alcohol intake, physical activity, age, family history, red meat consumption, aspirin use, fiber intake, and smoking history. Interestingly, more than 86% of the women who consumed more than 400 mcg/d took a multivitamin that contained large quantities of folic acid. This latter fact gives more evidence that supplementation is needed for most Americans to obtain the optimum intake of about 800 mcg/d.

In the NHANES Follow-up Study (NHEFS),12 the relative risk for colon cancer of the men in the highest intake group (> 239 mcg/d in diet) was 60% less than those men in the lowest intake group (< 103.3 mcg/d). While the direction of change was the same for women (a 36% risk reduction), it did not reach significance, perhaps because of the smaller number of cases of colon cancer in this group of women. This study suffers from lack of accounting for vitamin use and smoking.

In the Health Professionals Follow-Up Study, the hypothesis was that alcohol, which antagonizes methyl group metabolism, and low dietary intake of factors (folate and methionine) that facilitate methyl group donation, would increase the risk of colon cancer.13 The relative risk for these methyl donor-deficient conditions was 3.30, again supporting the indication that high-folate diets or supplement use can reduce the risk of colon cancer.

Other studies conducted for other purposes or that were less well-controlled support the indication that high-folate intake reduces the risk of clinically evident colon and rectal cancers.9,10,14 Even a study of a genetic mutation that limits methyl group availability showed an increased risk of colon cancers in the presence of substantial alcohol intake.15 Thus, it appears likely that obtaining folate at a level of about 800 mcg/d from diet or supplements for 15 years decreases the risk of clinically evident colon and rectal cancers by 30-60%.

Adverse Effects

Supplementation with folic acid is safe. Folate toxicity is so rare that I could not find case reports of such when folate is taken in concert with vitamins B6 and B12. No human toxicity has been reported with intakes of less than 2,000 mcg/d.

There have been rare cases of exacerbation of vitamin B12 deficiency reported with high doses of folic acid.16 This may be a concern in the elderly patient: Some data suggest that many elderly people have evidence of early vitamin B12, B6, or folate deficiency despite hav-ing normal serum vitamin concentrations.17 Folic acid supplementation may make it more difficult to diag- nose vitamin B12 deficiency using screening blood cell panels.

Drug Interactions

There are several drugs that can interact with folic acid. Patients treated with the antiseizure medication phenytoin may have a decrease in phenytoin levels, although at supplement doses this is unlikely to increase seizure frequency.16 Folic acid may reduce the efficacy of methotrexate used for rheumatoid arthritis and other medical conditions.

Conclusion

If reduction of arterial aging and homocysteine levels were not enough motivation to supplement the diet with 800 mcg of folic acid a day, reduced risk of clinical colon and rectal cancer should be. I believe these data support this level of supplementation, at least pending intervention studies that indicate risk greater than benefit.18,19 The available data are strong enough to make the burden of disproving the hypothesis necessary before the recommendation to supplement with folate is withdrawn.

Recommendation

We should be taking and prescribing vitamin B9 (folate), and vitamins B6 and B12 to decrease homocysteine levels. Supplementation decreases the risk of all arterial aging-phenomena heart disease, stroke, memory loss, impotence, and probably wrinkling of the skin as well.20-22 The recommended daily dose of folate from diet and supplements for this preventive benefit is about 800 mcg (plus about 5 mg of B6 and at least 25 mcg of B12). 

Dr. Roizen is Professor of Anesthesia and Critical Care and Professor of Medicine, SUNY Upstate Medical University, Syracuse, NY.

References

1. Jacques PF, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-1454.

2. MRC Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-137.

3. Sorrentino MJ. Folic acid for the secondary prevention of heart disease. Altern Med Alert 1999;2:49-53.

4. Wong WY, et al. Effects of folic acid and zinc sulfate on male factor subfertility: A double-blind, randomized, placebo-controlled trial. Fertil Steril 2002;77:491-498.

5. Duthie SJ. Folic-acid-mediated inhibition of human colon-cancer cell growth. Nutrition 2001;17:736-737.

6. Peters GJ, Jansen G. Folate homeostasis and antiproliferative activity of folates and antifolates. Nutrition 2001;17:737-738.

7. Choi SW, Friso S. Is it worthwhile to try different coenzymatic forms of folate in future chemoprevention trials? Nutrition 2001;17:738-739.

8. Choi SW, Mason JB. Folate and carcinogenesis: An integrated scheme. J Nutr 2000;130:129-132.

9. Freudenheim JL, et al. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 1991;20: 368-374.

10. Giovcannucci E, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:875-884.

11. Giovannucci E, et al. Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study. Ann Intern Med 1998;129:517-524.

12. Su LJ, Arab L. Nutritional status of folate and colon cancer risk: Evidence from NHANES I epidemiologic follow-up study. Ann Epidemiol 2001;11:65-72.

13. Giovannucci E, et al. Alcohol, low-methionine—low-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995;87:265-273.

14. Smith-Warner SA, et al. Fruits, vegetables and adenomatous polyps. Am J Epidemiol 2002;155:1104-1113.

15. Ma J, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 1997;57:1098-1102.

16. Campbell NR. How safe are folic acid supplements? Arch Intern Med 1996;156:1638-1644.

17. Naurath HJ, et al. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet 1995;346:85-89.

18. Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: Clinical applications. JAMA 2002;287:3127-3129.

19. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: Scientific review. JAMA 2002;287:3116-3126.

20. Eikelboom JW, et al. Homocyst(e)ine and cardiovascular disease: A critical review of the epidemiologic evidence. Ann Intern Med 1999;131:363-375.

21. Rimm EB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:359-364.

22. Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trails. BMJ 1998; 316:894-898.