Background: As a mediator of one-carbon transfer reactions, folate is an essential cofactor in nucleotide biosynthesis. Interruption of intracellular folate metabolism and the consequent inhibition of tumor growth has been the basis for chemotherapy using antifolates and 5-fluorouracil (5FU). A growing body of evidence suggests that folic acid (FA; the synthetic form) may promote the progression of established colorectal (pre)neoplastic lesions. Folate blood levels in North America have dramatically increased over the past decade owing to FA fortification and widespread supplement use. Furthermore, over 50% of newly diagnosed colorectal cancer patients use vitamin supplements containing FA in addition to chemotherapeutic agents whose mechanisms of action are based on interruption of folate metabolism. This study therefore investigated whether FA supplementation can affect chemosensitivity of colon cancer cells to 5FU, the cornerstone of colorectal cancer treatment, in vivo. Methods: Male athymic nude mice were placed on the control diet containing 2 mg FA/kg diet and were inoculated with human HCT116 colon cancer cells. When xenografts were established, the animals were randomized to receive a diet containing 2, 8, or 25 mg FA/kg diet for eight weeks. Within each diet group, the animals were further randomized to receive saline vehicle or 5FU (20 mg/kg) + leucovorin (1 mg/kg) for five days. The primary endpoints were the rate of xenograft growth and the final volume. At necropsy, blood was collected and xenografts were harvested and evidence of metastasis was determined. Results: Plasma folate concentrations of animals on the 2 mg FA diet were significantly lower than those of animals fed the 8 and 25 mg FA diets (p<0.05). Xenograft folate concentrations significantly reflected the supplemental levels of FA in a dose-responsive manner (p=0.002). The effect of dietary levels of FA and 5FU alone were not significant, p=0.907 and p=0.193, respectively, but the interaction effect was significant (p<0.007). 5FU was beneficial only to animals fed the 2 mg FA diet (p<0.0001). In contrast, animals fed the 8 mg FA diet fared worse on 5FU (p=0.048) whereas animals fed the 25 mg FA diet demonstrated no effect of 5FU (p=0.31). All animals exhibited macroscopically evident lymph node involvement, but no distant metastases, irrespective of dietary levels of FA. Conclusion: Our data suggests that FA supplementation may adversely affect chemosensitivity to 5FU chemotherapy, although a dose-responsive relationship was not evident. Results of this study pose a legitimate public health concern given the drastically increased intake of FA from supplements, particularly among recently diagnosed colorectal cancer patients and from mandatory fortification. Further studies are warranted to confirm our findings and to elucidate the underlying mechanisms.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5432. doi:1538-7445.AM2012-5432