Since the late 1990s, the food supply of the United States, Canada, and other countries has been fortified with folic acid to lower the incidence of neural tube defects (e.g., spina bifida, anencephaly). This fortification program has been highly successful in reducing both the prevalence of folate deficiency in the general population1,2 and the incidence of neural tube defects.3 The success of the fortification program, however, has created a situation of excess folic acid consumption by a significant percentage of the general population, the negative ramifications of which, if any, are as yet undetermined. Geometric mean serum folate levels have more than doubled in the US population (from ∼12 to ∼30 nmol/L)4 and the prevalence of folic acid supplement users with intakes above the upper tolerable intake level (>1 mg folic acid/day) has increased from ∼1% to ∼11%.5 Because folate deficiency and anti-folate drugs are known to retard or prevent the proliferation of tumors, some have raised the question of whether excess folic acid in the food supply may promote malignant progression.6 Indeed, a recent analysis of data from the U.S. and Canada suggests that folic acid fortification may have increased the incidence of colorectal cancer by as much as 10%.7 Most cancers develop through a series of stages or transformations from normal to neoplasia in situ, invasive carcinoma, and ultimately metastasis. Folate is potentially an important mediator of progressive changes in tumor cell biology, based on its central role in one-carbon metabolism (Figure 1). Folate, in the form of 5,10-methylenetetrahydrofolate, has three major biochemical fates. First, it serves as the one-carbon donor in the conversion of deoxyuridine to thymidylate, which in turn is incorporated into DNA. Folate deficiency causes inhibition of this reaction, which can result in uracil misincorporation into DNA.8 DNA …

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