Chemoprevention of mammary carcinogenesis by 1alpha-hydroxyvitamin D(5), a synthetic analog of Vitamin D.

摘要

Numerous analogs of Vitamin D have been synthesized in recent years with the hope of generating a compound that retains the anticarcinogenic activity of Vitamin D without causing any toxicity. We synthesized such an analog, 1alpha-hydroxy-24-ethylcholecalciferol [1alpha-hydroxyvitamin D(5) or 1alpha(OH)D(5)], and showed that it was tolerated by rats and mice at a much higher dose than 1alpha,25 dihydroxy cholecalciferol [1alpha,25(OH)(2)D(3)]. This property makes it a prime candidate for chemoprevention studies. In the mouse mammary gland organ culture (MMOC), 1alpha(OH)D(5) inhibited carcinogen-induced development of both mammary alveolar and ductal lesions. In vivo carcinogenesis study showed statistically significant reduction of tumor incidence and multiplicity in N-methyl-N-nitrosourea (MNU)-treated rats that were fed 25-50&mgr;g 1alpha(OH)D(5)/kg diet. There were no adverse effects on plasma calcium concentrations. In order to determine if the effect of 1alpha(OH)D(5) would be selective in suppressing proliferation of transformed cells, its effects on cell growth and proliferation were compared between BT474 (cancer) and MCF12F (non-tumorigenic) human breast epithelial cells. Results showed that 1alpha(OH)D(5) induced apoptosis and cell cycle G1 phase arrest in BT474 breast cancer cells without having any effects on proliferation of the MCF12F cells. In addition, in MMOC it had no growth inhibitory effects on normal epithelial cell proliferation in the absence of carcinogen. Similarly, non-tumorigenic human breast epithelial cells in explant culture did not respond to 1alpha(OH)D(5), whereas treatment with 1alpha(OH)D(5) induced cell death in the explants of cancer tissue. These results collectively indicate that 1alpha(OH)D(5) selectively induced apoptosis only in transformed cells but not in normal breast epithelial cells. Interestingly, the growth inhibitory effects of 1alpha(OH)D(5) were observed in Vitamin D receptor positive (VDR(+)) breast cancer cells, but not in highly metastatic VDR(-) breast cancer cells, such as MDA-MB-435 and MDA-MB-231, suggesting that 1alpha(OH)D(5) action may be mediated, in part, by VDR.