Rationale for the development and current status of calcitriol in androgen-independent prostate cancer

Calcitriol, the principal active metabolite of vitamin D, has significant antineoplastic activity in pre-clinical models of prostate cancer and many other tumor types. Reported mechanisms of activity include inhibition of proliferation and cell cycle arrest, induction of apoptosis, and reduction of invasiveness and angiogenesis. Different mechanisms may be responsible in different tumor types and under different experimental conditions. Importantly, preclinical data suggest that calcitriol acts in a synergistic and/or additive manner when combined with antineoplastic agents that are relevant to prostate cancer, including dexamethasone and several classes of cytotoxic agents. The antineoplastic effects of calcitriol occur at concentrations that substantially exceed the normal physiologic range and cannot be safely achieved with conventional daily dosing. Intermittent administration of calcitriol has allowed significant dose escalation. In combination with weekly docetaxel, the agent produced encouraging results in a single-institution phase II study. An international placebo-controlled randomized trial that is currently under way will provide more robust information about the safety and efficacy of this combination.