OXY-16-ENE-23-YNE-26,27-HEXAFLUOROCHOLECALCIFEROL, A NONCALCEMIC ANALOG OF 1-ALPHA,25-DIHYDROXYVITAMIN D-3, INHIBITS AZOXYMETHANE-INDUCED COLONIC TUMORIGENESIS

Vitamin D-3 and its metabolites, particularly 1 alpha,25-dihydroxyvita min D-3 (1 alpha,25(OH)(2)D-3), have received increasing attention as potential anticarcinogens in the prevention of cancers in a number of organs, including the colon. These agents, however, have the potential to induce hypercalcemia, thus limiting their practical use for these purposes. In the present studies it was, therefore, of interest to det ermine whether dietary supplementation with 1 roxy-16-ene-23-yne-26,27 -hexafluorocholecalciferol (RO24-5531), a recently synthesized apparen tly noncalcemic analogue of 1 alpha,25(OH)(2)D-3, inhibited colon canc er induced by azoxymethane (AOM). Rats were placed on a standard diet or fed this diet with supplemental RO24-5531 (2.5 nmol/kg feed) before and during (initiation arm), or after AOM or vehicle administration ( postinitiation arm). After 34 weeks of study, animals in each group we re sacrificed, and their colons were removed and examined macroscopica lly and microscopically for the presence of tumors. At the time of sac rifice, the animals' serum calcium, phosphorus, 25-hydroxyvitamin D-3 and 1 alpha,25(OH)(2)D-3, levels were also analyzed. The results of th ese studies demonstrated that dietary RO24-5531 supplementation during the initiation arm of these experiments significantly reduced (by 70% ) the incidence of AOM-induced colonic tumors compared to rats on the standard diet without RO24-5531. Moreover, this dietary regimen abolis hed the development of adenocarcinomas in this model. Although there w as also a trend for dietary RO24-5531 supplementation during the posti nitiation arm of this study to reduce the incidence of colon tumors, t his did not reach statistical significance (P > 0.05). In addition, ne ither dietary RO24-5531 supplementation regimen significantly influenc ed the animals' rates of growth or their serum levels of calcium, phos phorus, or 25-hydroxyvitamin D-3. These studies, therefore, demonstrat e for the first time that supplemental dietary RO24-5531 is a chemopre ventive agent in the AOM model of experimental colonic carcinogenesis. They also suggest that this agent may ultimately prove useful in clin ical colon cancer chemopreventive trials.