Effective
chemotherapy for
pancreatic cancer is urgently needed. The aim of this study was to compare the anti-proliferative activity on
pancreatic cancer cell lines of the
vitamin D(3) analog, 22-oxa-1,25-dihydroxyvitamin D(3),
maxacalcitol, with that of
1,25-dihydroxyvitamin D(3),
calcitriol, with analysis of
vitamin D receptor status and the G(1)-phase cell cycle-regulating factors. Antiproliferative effects of both agents were compared using the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method and by measuring the
tumor size of xenografts inoculated into athymic mice. Scatchard analysis of
vitamin D receptor contents, and mutational analysis of receptor
complementary DNA were performed. Levels of expression of
cyclins,
cyclin-dependent kinases and
cyclin-dependent kinase inhibitors, p21 and p27, were analysed by western blotting. In vitro,
maxacalcitol and
calcitriol markedly inhibited the proliferation and caused a G(1) phase cell cycle arrest with the appearance of numerous domes. In vivo,
maxacalcitol inhibited the growth of BxPC-3 xenografts more significantly than
calcitriol, without inducing
hypercalcemia. Responsive cells had abundant functional
vitamin D receptors. However, Hs 766T, showing no response to either agent, had the second highest receptor contents with no abnormalities in its primary structure deduced by receptor
complementary DNA. In the responsive cells, p21 and p27 were markedly up-regulated after 24h of treatment with both agents. In non-responsive cells, no such changes were observed. In conclusion,
maxacalcitol and
calcitriol up-regulate p21 and p27 as an early event, which in turn could block the G(1)/S transition and induce growth inhibition in responsive cells, and
maxacalcitol may provide a more useful tool for the
chemotherapy of
pancreatic cancer than
calcitriol because of its low toxicity.