We have demonstrated that the most active vitamin D moiety 1,25 dihydroxycholecalciferol (calcitriol) has significant antiproliferative activity in vivo and in vitro. Calcitriol induces G0/G1 arrest, modulates p27/p21, induces apoptosis and enhances the antitumor activity of cisplatin, carboplatin, paclitaxel and docetaxel. In vitro and in vivo, dexamethasone (dex) potentiates calcitriol-mediated antitumor activity and vitamin D receptor (VDR) ligand binding in vitro and in vivo and enhances VDR protein expression. Calcitriol/dex also suppress activated mitogen-activated protein kinase (MAPK), Ert 1/2) activity and phosphorylated Akt (P-Akt). In a phase II clinical trial of hormone refractory prostate cancer with high dose oral calcitriol and dex, we observed a 50 percent reduction in serum prostate specific antigen (PSA) in 28 percent of patients with no hypercalcemia; modulation of VDR and other potential markers of calcitriol activity in peripheral blood monocytes. We have preliminary data indicating that calcitriol and dex induces apoptosis, modulates cell cycle, decreases P-Erk 1/2 and P-Ark and significantly up-regulated VDR expression of tumor-derived endothelial cells (TDEC) as compared to endothelial cells isolated from normal tissues (aortic). These studies suggest that the mechanism(s) of calcitriol/dex antitumor activity may involve effects on intratumor vasculature. We propose to examine this hypothesis by the following Specific Aims: 1) to determine the mechanisms involved in calcitriol/dex effects in TDEC isolated from prostate tumors as compared to normal by examining: a) effects on apoptosis and cell cycle; b) effects on invasiveness, motility, and angiogenesis; and c) whether activities require calcitriol binding to the VDR; 2) To determine the prostate tumor models the role of TDEC in calcitriol/dex antitumor effects by determining: a) effects on the vasculature within the tumor; b) effects on TDEC isolated from animals treated with calcitriol; and c) whether a relationship exists between modulation of effects on TDEC and antitumor effects and 3) To evaluate oral calcitriol (12mg QDx3) and/or dex (4mg QDx4) administered weekly x 4 to patients with localized prostate cancer immediately prior to prostatectomy to determine: a) effects on tumor endothelial cells; b) effects of cell cycle status, apoptosis markers and prostatic intraepithelial neoplasia (PIN) and c) prostate specific antigen (PSA) response.
Showing the most recent 10 out of 48 publications
