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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA095045-01
Application #
6461127
Study Section
Special Emphasis Panel (ZRG1-ET-1 (01))
Program Officer
Xie, Heng
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$365,730
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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