Novel Paclitaxel Copolymer for Treatment of Androgen-Independent Prostate Cancer Bone Metastases
Abstract
The human prostatic carcinoma cell lines, PC-3 and bone metastases-derived NDA-PCa-2a and MDA-PCa-2b, are susceptible to apoptotic induction in vitro by Taxol, poly-L-(glutamic acid)-paclitaxel (PGA-TXL) and hyaluronic acid-paclitaxel (HA-TXL). Paclitaxel-induced activation of apoptosis can be blocked at the leel of caspase-3 induction by sphingosine-1-phosphate (S-I-P). Dimethyl-sphingosine (DMSP) effectively inhibits sphingosine kinase (SpK), reducing cellular S-I-P levels, and thereby facilitating maturation of apoptotic signals. DMSP causes rapid expression of Annexin in PC-3 cells, and induces TUNEL-positive cells; the latter, but not the former, is inhibited by the broad-spectrum inhibitor, Z-VAD. We have also shown that the mitochondria are proximal targets of DMSP-mediated apoptosis in PC-3 cells, resulting in rapid loss of mitochondrial membrane potential, rapid cytochrone C mobilization, and rapid caspase activation, including caspase-9, these responses are unaffected by BCL-2, of significant relevance to apoptosis induction in metastatic prostate cancer. We will continue with the planned tasks, but will also attempt to merge them with strategies to systemically deliver DMSP to prostatic tumor xenografts, and thereby enhance paclitaxel-induced apoptosis and reverse tumor angiogenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2004
- Accession Number
- ADA423020
Entities
People
- Jim Klostergaard
Organizations
- The University of Texas MD Anderson Cancer Center