Vitamin D, 1,25 dihydroxycholecalciferol (calcitriol) has significant antiproliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates p27 and p21, induces cleavage of caspase 3, MEK, and PARP, inhibits P-Akt and significantly increases MEKK-1 and the p53 homologue, p73. Also, calcitriol significantly enhances the in vitro and in vivo antitumor efficacy of platinum analogues and taxanes. In vitro and in vivo, dexamethasone (dex) potentiates calcitriol-mediated antitumor activity through the vitamin D receptor (VDR). In a phase II trial in androgen-independent prostate cancer (AIPC) with high dose oral calcitriol and dex, we observed a 50% reduction in serum prostate specific antigen (PSA) in 28% of patients. Calcitriol/dex antitumor effects were also noted in men with localized disease with a rising PSA following prostatectomy or irradiation. From the pharmacokinetic (pk) data from a number of trials, increasing oral doses of calcitriol did not result in higher serum calcitriol levels; suggesting a potential decrease in bioavailability. Ketoconazole, an inhibitor of CYP24, the enzyme responsible of catabolism of calcitriol, can synergize with calcitriol and dex both in vitro and in vivo in the prostate PC-3 model by enhancing antitumor effects with decreases in CYP24 levels. Therefore, glucocorticoids differentially modulate and enhance calcitriol-mediated effects and have significant therapeutic implications. Therefore, we propose to examine the potential efficacy and mechanisms of calcitriol in combination with glucocorticoids both clinically and pre-clinically by addressing the following specific aims: 1) to determine the modulation of the molecular events in the calcitriol signaling pathway in vitro and in vivo in tumor models of calcitriol/dex/ketoconazole; 2) to evaluate an escalating single dose of iv calcitriol weekly in combination with continuous low dose (200 mg TID) or high dose (400mg TID) ketoconazole + dexamethasone (0,5mg QD) in patients with advanced cancer through the conduct of a two stage, phase I clinical trial; 3) to determine the mechanisms of the glucocorticoid enhanced antitumor effect of calcitriol in vitro and in vivo and 4) to examine in a phase II trial the effect of a single dose of iv calcitriol weekly (dose to be determined from the ongoing phase I trial) and dexamethasone (4mg, QDx4) weekly for a month prior to combining with in men with androgen independent prostate cancer.
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