Inhibition of Development of N, N′‐Dimethylhydrazine‐induced Rat Colonic Aberrant Crypt Foci by Pre, Post and Simultaneous Treatments with 24R,25‐Dihydroxyvitamin D(3)

It has recently been reported that new vitamin D(3) derivatives can exert inhibitory effects on colon carcinogenesis in rats. In the present study the chemopreventive potential of 24R,25‐dihydroxyvitamin D(3) (24ff,25(OH)(2)vitainin D(3)) was assessed in a murine model of colon carcinogenesis. In experiment 1, male 6‐week‐old F344 rats were administered N(2)N‐dimethylhydrazme (DMH) 20 mg/kg s.c. once a week 4 times. The rats were fed 24R,25(OH)(2)vitaniin D(3) 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)(2)vitamin D(3) was found to have reduced the total numbers of ACF and significantly inhibited the development of foci. After 16 weeks, numbers of foci with ≥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)(2)vitaniin D(3) 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 D(3) metabolite than in the controls. In experiment 2, the effect of 24R,25‐(OH)(2)vitamin D(3) 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)(2)vitamin D(3). The results suggest that 24R,25(OH)(2)vitamin D(3) is a cancer chemopreventive agent which may suppresses DMH induction of lesions and their subsequent development via an antiproliferative action.