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Departments of Medicine and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada and Division of Gastroenterology, St. Michael's Hospital, Toronto, Ontario, Canada
2 To whom correspondence should be addressed. E-mail: youngin.kim{at}utoronto.ca.
Folate, a water-soluble B vitamin and important cofactor in 1-carbon transfer, is an important nutritional factor that may modulate the development of colorectal cancer. Epidemiologic and clinical studies indicate that dietary folate intake and blood folate levels are inversely associated with colorectal cancer risk. Collectively, these studies suggest an 
40% reduction in the risk of colorectal cancer in individuals with the highest dietary folate intake compared with those with the lowest intake. Animal studies using chemical and genetically predisposed rodent models have provided considerable support for a causal relationship between folate depletion and colorectal carcinogenesis as well as a dose-dependent protective effect of folate supplementation. However, animal studies have also shown that the dose and timing of folate intervention are critical in providing safe and effective chemoprevention; exceptionally high supplemental folate levels and folate intervention after microscopic neoplastic foci are established in the colorectal mucosa promote rather than suppress colorectal carcinogenesis. These animal studies in conjunction with clinical observations suggest that folate possesses the dual modulatory effects on carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect whereas folate supplementation has a promoting effect on progression of established neoplasms. In contrast, folate deficiency in normal epithelial tissues appears to predispose them to neoplastic transformation, and modest levels of folate supplementation suppress the development of tumors in normal tissues. Notwithstanding the limitations associated with animal models, these animal studies suggest that the optimal timing and dose of folate intervention need to be established for safe and effective chemoprevention in humans.
KEY WORDS: • folate • colorectal cancer • chemoprevention • animal models
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