Prevention of N-Methyl-N-Nitrosourea-Induced Mammary Carcinogenesis in Rats by 1alpha-Hydroxyvitamin D5

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Abstract
Background: Although the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D3, 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 D3 are poorly effective against mammary carcinogenesis. We synthesized an analogue of vitamin D5, 1α-hydroxy-24-ethylcholecalciferol (1α-hydroxyvitamin D5), which was less calcemic than 1,25-dihydroxyvitamin D3 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 1α-hydroxyvitamin D5 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 1α-hydroxyvitamin D5 for an additional 105 days. Tumor incidence and multiplicity were determined, and plasma concentrations of calcium and phosphorus were measured. The efficacy of 1α-hydroxyvitamin D5 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 1α-hydroxyvitamin D5 at 25 μg/kg diet and 50 μg/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 D5 analogue was effective during both the initiation and the promotion stages of mammary lesion formation in organ culture. Conclusion: Our findings indicate that 1α-hydroxyvitamin D5 reduces the incidence of mammary carcinogenesis in vivo. This analogue appears to be a good candidate for further development as a chemopreventive agent.

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