1,25-Dihydroxyvitamin D (
calcitriol), the most active metabolite of
vitamin D, has significant
antineoplastic activity in preclinical models. Several mechanisms of activity have been proposed. These include inhibition of proliferation associated with cell cycle arrest and, in some models, differentiation, reduction in invasiveness and angiogenesis, and induction of apoptosis. Proposed mechanisms differ between
tumor models and experimental conditions, and no unifying hypothesis about the mechanism of
antineoplastic activity has emerged. Synergistic and/or additive effects with cytotoxic
chemotherapy, radiation, and other
cancer drugs have been reported. Significantly supraphysiological concentrations of
calcitriol are required for
antineoplastic effects. Such concentrations are not achievable in patients when
calcitriol is dosed daily due to predictable
hypercalcemia and hypercalcuria; however, phase I trials have demonstrated that intermittent dosing allows substantial dose escalation and has produced potentially therapeutic peak
calcitriol concentrations. Recently, a phase II study reported encouraging levels of activity for the combination of high-dose
calcitriol and
docetaxel administered on a weekly schedule in patients with
androgen-independent
prostate cancer. This regimen is now under study in a placebo-controlled randomized trial in
androgen-independent
prostate cancer and in phase II studies in several other
tumor types. Further work is needed to elucidate the molecular mechanisms of
antineoplastic activity and optimal clinical applications of
calcitriol in
cancer.