Carcinogenesis Advance Access published online on June 18, 2009
Carcinogenesis, doi:10.1093/carcin/bgp152
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Effect of folic acid supplementation on the progression of colorectal aberrant crypt foci
Departments of Nutritional Sciences (GML, YIK), Laboratory Medicine and Pathobiology (AM), Medicine (KJS, YIK), Pharmacology and Toxicology (FD), University of Toronto, Toronto, Ontario, Canada, M5S 1A8
Department of Pathology (AM), Humber River Regional Hospital, Toronto, Ontario, Canada, M9N 1N8
Statistical Consultant (RC), Toronto, Ontario, Canada, M4E 3K7
Division of Gastroenterology (YIK), St. Michael's Hospital, Toronto, Ontario, Canada, M5B 1W8
Correspondence/Reprint requests: Young-In Kim, MD, Room 7258, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada, M5S 1A8; Telephone: 416-978-1183; Fax: 416-978-8765; E-mail: youngin.kim{at}utoronto.ca
Whether or not folic acid supplementation promotes the progression of colorectal preneoplastic lesions to cancer is an important public health issue, given mandatory fortification and widespread supplemental use of folic acid in North America. We investigated the effect of folic acid supplementation on the progression of aberrant crypt foci (ACF), the earliest precursor of colorectal cancer. Male Sprague-Dawley rats (n = 152) were placed on a control diet (2mg folic acid/kg diet) at weaning and ACF were induced by azoxymethane. Six weeks post-ACF induction, rats were randomized to receive 0, 2, 5 or 8 mg folic acid/kg diet. At 34 weeks of age, rats were sacrificed, and colorectal tumor paremeters, plasma folate and homocysteine (a sensitve inverse indicator of tissue folate status) concentrations, and rectal epithelial proliferaiton were determined. Although the number of ACF increased as dietary folic acid levels increased (p = 0.015), the incidence of colorectal tumors did not differ significantly among the 4 dietary groups. However, tumor multiplicity was positively correlated with dietary folic acid levels (r = 0.32; p = 0.002) and inversely with plasma homosyteine concentrations (r = -0.32; p = 0.005). Tumor burden was positively correlated with dietary folic acid levels (r = 0.35; p = 0.001) and plasma folate concentrations (r = 0.33; p = 0.008) and inversely with plasma homocysteine concentrations (r = -0.42; p<0.001). Rectal epithelial proliferation was positively correalted with dietary folic acid levels (r=0.39; p<0.001) and plasma folate concentrations (r=0.34; p<0.001) and inversely with plasma homocysteine concentrations (r= -0.37; p<0.001). Our data suggest that folic acid supplementation may promote the progression of ACF to colorectal tumors.
Received March 31, 2009; revised June 1, 2009; accepted June 9, 2009.