) We propose to examine the hypothesis that folate supplementation of 1,000 micrograms daily for 3 years will reduce the recurrence of colorectal adenomas, precursors of cancers, among patients who have had adenomas removed. Specifically, we propose to conduct a double-blinded, randomized, intervention trial among 1,000 individuals within two ongoing cohort studies, the Health Professionals Follow-Up Study and the Nurses' Health Study. We also plan to examine whether any influence of folate is modified by various factors, including baseline folate and vitamin B12 levels, aspirin use, family history of colorectal cancer, and intakes of alcohol and methionine. Within our cohorts, this proposed trial can be conducted in a very cost-efficient manner because recruitment costs are minimal, folic acid and placebo tablets will be provided gratis by Lederle Pharmaceuticals, follow-up mechanisms are already established, and colonoscopic procedures will be conducted as part of the routine medial care by the subjects' physicians. In addition, because these participants are health professionals who have already demonstrated outstanding commitment to long-term studies, we anticipate excellent compliance rates. Data based on these cohorts, the first two prospective studies of colorectal adenomas, show that folate intake, primarily from multivitamin supplements, is inversely related to risk of colorectal adenoma. A plausible biological mechanism related to DNA methylation also supports this relationship, and we observe similar relations with colorectal cancer. Given the high rates of colorectal cancer and the high prevalence of folate deficiency in the population, we believe that this large or high-risk groups can be targeted through various means, including food fortification, supplementation or dietary education. Thus, we believe that it is crucial to prove in a randomized clinical trial setting that folate supplementation reduces the occurrence of colorectal neoplasia.
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