title: 1 alpha,25-Dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol, a noncalcemic analogue of 1 alpha,25-dihydroxyvitamin D3, inhibits azoxymethane-induced colonic tumorigenesis.
abstract: Vitamin D3 and its metabolites, particularly 1 alpha,25-dihydroxyvitamin D3 (1 alpha, 25(OH)2D3), 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 determine whether dietary supplementation with 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (RO24-5531), a recently synthesized apparently noncalcemic analogue of 1 alpha,25(OH)2D3, inhibited colon cancer 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 were sacrificed, and their colons were removed and examined macroscopically and microscopically for the presence of tumors. At the time of sacrifice, the animals' serum calcium, phosphorus, 25-hydroxyvitamin D3 and 1 alpha,25(OH)2D3 levels were also analyzed. The results of these 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 abolished the development of adenocarcinomas in this model. Although there was also a trend for dietary RO24-5531 supplementation during the postinitiation arm of this study to reduce the incidence of colon tumors, this did not reach statistical significance (P > 0.05). In addition, neither dietary RO24-5531 supplementation regimen significantly influenced the animals' rates of growth or their serum levels of calcium, phosphorus, or 25-hydroxyvitamin D3. These studies, therefore, demonstrate for the first time that supplemental dietary RO24-5531 is a chemopreventive agent in the AOM model of experimental colonic carcinogenesis. They also suggest that this agent may ultimately prove useful in clinical colon cancer chemopreventive trials.
authors.affiliation: Department of Medicine, University of Chicago Hospitals and Clinics, Pritzker School of Medicine, Illinois 60637, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Wali
authors.forename: M
authors.initials: M
authors.lastname: Bissonnette
authors.forename: S
authors.initials: S
authors.lastname: Khare
authors.forename: J
authors.initials: J
authors.lastname: Hart
authors.forename: M D
authors.initials: MD
authors.lastname: Sitrin
authors.forename: T A
authors.initials: TA
authors.lastname: Brasitus
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001397:Azoxymethane; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D016588:Anticarcinogenic Agents; C086492:Ro 24-5531; D002117:Calcitriol; D001397:Azoxymethane