Modulation of Paclitaxel Antitumor Effects by Calcitriol: Preclinical Studies of Mechanism, Toxicity and Efficacy in Prostate Cancer
Abstract
1,25-DIHYDROXYCHOLECALCIFEROL CALCITRIOL HAS ANTIPROLIFERATIVE ACTIVITY IN VITRO AND IN VIVO AND ENHANCES THE ANTITUMOR ACTIVITY OF CONVENTIONAL CYTOTOXIC AGENTS SUCH AS CISPLATIN AND CARBOPLATIN. In this study, we examined the antitumor effects of calcitriol in combination with paclitaxel in animal tumor model systems and in a Phase I clinical trial. Treatment of PC-3 and SCC cells in vitro with calcitriol 24h prior to paclitaxel reduced clonogenic potential compared to either agent alone. Treatment of tumor bearing animals with calcitriol prior to paclitaxel resulted in greater growth inhibition than was achieved with either agent alone. Paclitaxel induced apoptosis in PC-3 cells as evidenced by the time-dependent accumulation of cells with hypodiploid DNA content and the loss of lull-length PARP. Paclitaxel effects were associated with the induction of p21 and loss of Bcl-2 expression. None of the measured molecular alterations induced by paclitaxel were further modulated by calcitriol. Calcitriol enhances the antitumor effects of paclitaxel in vitro and in vivo. In addition, paclitaxel and Zoledronate significantly decreased calcitriol mediated hypercalcemia in animal models. Clinically, patients with advanced tumors are being treated with weekly cycles of calcitriol (daily x3) and paclitaxel (day 3) and the trial continues to acrue patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1999
- Accession Number
- ADA384843
Entities
People
- Donald Trump
Organizations
- University of Pittsburgh