Vitamin D or 1,25-dihydroxycholecalciferol (1,25D3) inhibits proliferation, induces differentiation and modulates cell cycle control in a variety of normal and malignant cells. The applicants have demonstrated over the previous funding period that 1,25D3 or its analogs have significant anti-proliferative activity, arrest cells in G0/G1, induce expression of p27 and p21, induce PARP cleavage and enhance the anti-tumor activity of conventional chemotherapeutic agents. Dexamethasone (dex) enhances 1,25D3-mediated anti-proliferative effects and decreases 1,25D3 induced hypercalcemia: these activities may be mediated by effects on the VDr. In addition, they have completed a phase I trial with sc calcitriol in which they determined the MTD and calcitriol pharmacokinetics. The applicants propose to examine effects of 1,25D3 by the following specific aims 1) To examine the anti-tumor activity and the mechanisms involved with 1,25D3 in combination with carboplatin and/or paclitaxel by determining a) the optimum schedule- and time-dependent parameters, b) the role of apoptosis and intracellular Ca2+ changes for these effects, c) the role of cell cycle arrest, and d) the toxicities, MTD and carboplatin pharmacokinetics of calcitriol administered sc for 3 days before and after carboplatin in patients with advance solid tumors; 2) To examine the mechanisms involved in 1,25D3- mediated cell cycle arrest through a) effects on cell cycle check points, b) the role of p21 and p27, and c) the effect of calcitriol on cell cycle status, apoptosis, and VDR expression in prostate cancer patients treated with calcitriol prior to prostatectomy; and 3) To determine the role of glucocorticoids in 1,25D3-mediated activities by a) examining the effect of dex on enhanced anti-proliferative activity, b) on the down-modulation of VDR in the intestinal mucosa, and c) the effect of prednisone in combination with sc calcitriol on toxicity, the MTD and calcitriol pharmacokinetics in patients with advanced tumors.
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