A protective role of dietary vitamin D₃ in rat colon carcinogenesis

The aim of the present work was to gain insight into a putative anticancer effect of dietary vitamin D₃ (cholecalciferol) in a rat model of colon carcinogenesis. Male rats were assigned to three different dietary groups. The dietary regimens were based on a standard murine-defined diet (AIN- 76A) or a stress diet containing 20% fat, reduced Ca²⁺ concentration, a high phosphorus-to-Ca²⁺ ratio, and either low or high vitamin D₃ content. Colorectal cancer was induced by administration of the procarcinogen 1,2-dimethyl-hydrazine (DMH). Blood Ca²⁺, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], and 25-hydroxyvitamin D₃ [25(OH)D₃] levels were measured in DMH-treated rats and in respective weight- and age-matched dietary control groups. Colonic epithelial proliferation was assessed by determining thymidine kinase (TK) activity, bromodeoxyuridine (BrdUrd) incorporation into crypt cell DNA, and the mean labeling index along the colonic crypt continuum. Maintenance of rats on the stress diet either unmodified or supplemented with vitamin D₃ in the absence of carcinogen treatment provoked a time-dependent rise in colonic TK activity and hyperproliferation of colonic epithelium. DMH treatment of rats maintained on the standard diet caused a marked increase in the proliferative indexes of colonic epithelium and in expansion of the crypt proliferative compartment. TK activity and the crypt mitotic zone were significantly augmented in the animal group fed the stress diet. Supplementary vitamin D₃ abrogated the stress diet-enhanced colonic responses to the carcinogenic insult. Colon tumor multiplicity was fourfold higher in animals fed the stress diet than in animals maintained on a standard diet. The marked rise in colonic tumor multiplicity and adenocarcinoma incidence in rats fed the stress diet was obliterated by supplemental dietary vitamin D₃. Cumulatively, the present results indicate that dietary vitamin D₃ impedes the neoplastic process in murine large intestine and strengthen the view that inappropriate changes in dietary components and micronutrients are contributory determinants of colorectal cancer.