Modulation of Paclitaxel Antitumor Effects by Calcitriol: Preclinical Studies of Mechanism, Toxicity and Efficacy in Prostate Cancer
Abstract
Vitamin D or 1,25-dihydroxycholecalciferol (calcitriol)inhibits proliferation, induces differentiation and modulates cell cycle progression in a variety of normal and malignant cells. We demonstrated in the Dunning rate prostate cancer(Mat-Ly-Lu) and a human xenograft model (PC-3) that calcitriol has significant anti-proliferative activity, arrests cells in GO/G1, modulates expression of p27 and p21, induces PARP cleavage and significantly enhances the anti-tumor activity of conventional chemotherapeutic agents, especially paclitaxel. In addition, we have completed a phase I trial of high dose calcitriol in which we determined the MTD of subcutaneous calcitriol and calcitriol pharmacokinetics. Since paclitaxel has considerable potential as an agent for the therapy of prostate cancer and calcitriol potentiates paclitaxel and is active as a single agent, we propose to examine further the therapeutic potential of calcitriol by: (1) determining the schedule and time-dependent parameters of calcitriol and paclitaxel for optimum potentiating activity in MLL and PC-3 prostate cancer models; (2) determining the role of calcitriol in the induction of apoptosis and the role of changes in intracellular Ca + 2 in these activities; and (3) evaluating the toxicities, MTD, pharmacokinetics and pharmacodynamics and activity of paclitaxel and calcitriol when administered to patients with prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2001
- Accession Number
- ADA398149
Entities
People
- Donald Trump
Organizations
- University of Pittsburgh