Prevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats by 1α-hydroxyvitamin D5

Background: Although the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D-3, is a potent cell-differentiating agent, its use in cancer prevention or therapy is precluded because it induces excessive blood calcium levels (hypercalcemia), However, less calcemic or noncalcemic synthetic analogues of vitamin D-3 are poorly effective against mammary carcinogenesis. We synthesized an analogue of vitamin D-5, l alpha -hydroxy-24-ethylcholecalciferol (1 alpha -hydroxyvitamin D-5), which was less calcemic than 1,25-dihydroxyvitamin D-3 and prevented the development of precancerous lesions in mammary glands. Here, we evaluate its efficacy in an experimental rat mammary carcinogenesis model. Methods: Sprague-Dawley rats were treated with 1 alpha -hydroxyvitamin D-5 beginning 2 weeks before carcinogen treatment. Animals received an intravenous injection of N-methyl-N-nitrosourea at 80 days of age and continued to receive dietary 1 alpha -hydroxyvitamin D-5 for an additional 105 days, Tumor incidence and multiplicity were determined, and plasma concentrations of calcium and phosphorus were measured. The efficacy of 1 alpha -hydroxyvitamin D-5 at different stages of carcinogenesis was determined in mouse mammary gland organ culture. All statistical tests were two-sided. Results: The tumor incidence was reduced from 80% (95% confidence interval [CI] = 51.9%-95.7%) in control rats to 53.3% (95% CI = 26.6%-78.8%) and 46.6% (95% CI = 21.3%-73.4%) in rats treated with 1 alpha -hydroxyvitamin D-5 at 25 mug/kg diet and 50 mug/kg diet, respectively. The tumor multiplicity was reduced from 1.6 tumors per rat to 1.2 (95% CI for the difference = -0.45 to 1.25; P = .34) and 0.8 (95% CI for the difference = 0.14-1.46; P = .02), respectively. There was no statistically significant increase in the plasma calcium or phosphorus concentration at either dose level. The vitamin D-5 analogue was effective during both the initiation and the promotion stages of mammary Lesion formation in organ culture, Conclusion: Our findings indicate that 1 alpha -hydroxyvitamin D-5 reduces the incidence of mammary carcinogenesis in vivo. This analogue appears to be a good candidate for further development as a chemopreventive agent.