It has recently been reported that new
vitamin D3 derivatives can exert inhibitory effects on colon
carcinogenesis in rats. In the present study the chemopreventive potential of 24R,25-dihydroxyvitamin D3 (24R,25(
OH)2vitamin D3) was assessed in a murine model of colon
carcinogenesis. In experiment 1, male 6-week-old F344 rats were administered
N,N'-dimethylhydrazine (
DMH) 20 mg/kg s.c. once a week 4 times. The rats were fed 24R,25(
OH)2vitamin D3
at 10 ppm in the diet prior to (pre), together with (simultaneous) or after (post)
DMH treatment. Modifying effects were assessed using
aberrant crypt foci (ACF), putative preneoplastic lesions, as the end point markers in this model of colon
carcinogenesis. After 8 weeks, pre and more markedly simultaneous administration of 24R,25(
OH)2vitamin D3 was found to have reduced the total numbers of ACF and significantly inhibited the development of foci. After 16 weeks, numbers of foci with > or = 4 crypts, which are more likely to progress to
tumors, were significantly reduced. The most pronounced inhibition of ACF development was noted in rats fed the 24R,25(
OH)2vitamin D3 after
DMH administration. The reduction was particularly marked in the proximal colon. Blood levels of
calcium were not significantly increased over the control levels in groups administered
DMH and the
vitamin. Immunohistochemical staining showed numbers of
proliferating cell nuclear antigen-positive cells to be lower in the colonic epithelia of rats fed the
vitamin D3 metabolite than in the controls. In experiment 2, the effect of 24R,25(
OH)2vitamin D3 on the alterations in c-fos, c-myc and c-jun oncogene expression in response to
DMH administration was examined by northern blot analysis. The early increase in expression of
ornithine decarboxylase (ODC) activity was not altered by 24R,25(
OH)2vitamin D3. The results suggest that 24R,25(
OH)2vitamin D3 is a
cancer chemopreventive agent which may suppresses
DMH induction of lesions and their subsequent development via an antiproliferative action.