Studies in our laboratory demonstrate that vitamin D or 1,25- dihy6droxycholecalciferol (calcitriol) has significant anti proliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates expression of p27/p21, induces PARP cleavage, increases the bax/bcl-2 ratio and enhances the anti-tumor activity of cisplatin, carboplatin and paclitaxel. Dexamethasone (dex) potentiates calcitriol-mediated anti- tumor activity and vitamin D receptor (VDR) ligand binding in vitro and in vivo whereas equivalent doses of methylpredinsolone (mp) do not. Both dex and mp enhance VDR protein expression; however, calcitriol plus dex results in an increase in retinoid X receptor (RXR) alpha levels and calcitriol/mp decreases RXRalpha. Calcitriol/dex suppresses activity mitogen-activated protein kinase ( MAPK) activity while calcitriol/mp have no effect. In a phase II clinical trial of hormone refractory prostate cancer with oral calcitriol and dex, we observed a 50% reduction in prostate specific antigen (PSA) in 31% of patients with no hypercalcemia and a modulation of VDR from peripheral blood monocytes. We propose to determine the mechanisms of calcitriol and dex/mp interaction by the following specific aims: 1) To determine the mechanisms involved in glucocorticoid effects on tumor cells by examining: a) the role of steroid binding to the glucocorticoid receptor (GR); b) the differential role of RXR; and c) whether glucocorticoid effects require calcitriol binding to the VDR, modulate binding to the VDRE, and/or tumor model systems by determining: a) the effect on receptor (VDR/GR) and non-receptor (MAPK) mediated activities, and b) the role of RXR; and 3) To evaluate oral calcitriol and dex in hormone refractory prostate cancer through conduct of a phase I trial to determine: a) the maximum tolerated dose (MTD), toxicities and calcitriol pharmacokinetics, b) the clinical and PSA response, and 4) modulation of peripheral blood monocyte VDR, RXR and MAPK activity by calcitriol and calcitriol/dex.
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