Chemoprevention of chemically-induced mammary and colon carcinogenesis by 1α-hydroxyvitamin D5

Epidemiological data as well as experimental models yield evidence for a protective effect of vitamin D against the genesis of several types of cancers. Given its toxic properties at effective concentrations, numerous analogs of vitamin D have been developed. We synthesized an analog of vitamin D-5, 1 alpha-hydroxy-24-ethylcholechalciferol (1 alpha(OH)D-5) and previously reported on its anti-proliferative activities against several cancer cell lines. To further examine its chemopreventive potential, experiments were conducted to investigate the in vivo effects of 1 alpha(OH)D-5 using the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model. Results showed that 1 alpha(OH)D-5 (25 and 50 mu g/kg diet) decreased the incidence and multiplicity of mammary tumors in female Sprague-Dawley rats. In a subsequent study, the stage specific inhibition was investigated using the 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis model. While supplementation with of 1 alpha(OH)D-5 (40 mu g/kg diet) showed no significant effects during the initiation phase, tumor incidence during the promotional stage was significantly (p < 0.05) decreased by 37.5%. In the colon, 1 alpha(OH)D-5 (25 mu g/kg diet) was highly effective (p < 0.001) in inhibiting the development of azoxymethane (AOM)-induced Aberrant crypt foci (ACF) in CF-1 mice. Studies on the stage specific inhibitory effects of 1 alpha(OH)D-5 in the colon demonstrated that animals receiving 1 alpha(OH)D-5 (25 mu g/kg diet) during the initiation, promotion, and entire period had a reduction in ACF number of 71, 80 and 82%, respectively. Immunohistochemistry studies comparing the colons of animals receiving control versus 1 alpha(OH)D-5 supplemented diets showed that 1 alpha(CH)D-5 partly mediates its effects by regulating members of the oncogenic beta-catenin pathway. 1 alpha(OH)D-5 inhibited expression of beta-catenin and peroxisome proliferator-activated receptor beta, a beta-catenin-TCF-4 responsive gene, whereas it induced expression of VDR. Cumulatively, these studies support the chemopreventive properties of 1 alpha(OH)D-5 against the development of breast and colon cancers. (c) 2005 Elsevier Ltd. All rights reserved.