New Agents for Taxol-Resistant Ovarian Carcinoma
Abstract
Taxol resistance is an important issue in relapsing ovarian cancer. Two approaches to address this resistance include the use of drug copolymers and drug targeting. In this proposal, paclitaxel covalently coupled to backbones of poly(L-glutamic) acid (non- targeted) or hyaluronic acid (CD44 targeted) as prodrugs will be evaluated in CD44 over-expressing human ovarian carcinoma i.p. (orthotopic) xenografts. We have documented the high CD44 expression levels of several such models (HEY, NMP-l, SKOV-3 and SKOV-3i.p.). Further, all but the former present as multiifocal tumors in the peritoneal cavity, most relevant to an initially surgically debulked or relapsing patient. All lines were sensitive in vitro to Taxol and to PGA-TXL, and Taxol caused rapid activation of caspases. Further, we have shown that dimethyl-sphingosine, a potent inhibitor of sphingosine kinase that catalyzes the formation of pro-survival/anti-apoptotic sphingosine-l-phosphate, causes supra-additive cytotoxic interactions with Taxol on these lines. We will compare the antitumor efficacy of PGA-TXL and HA-TXL in these CD44 over-expressing ovarian tumor models, and also determine whether dimethyl-sphingosine can further reduce the apoptotic threshold in these tumors. These approaches may be important new tactics in addressing ovarian tumor chemoresistance.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA424595
Entities
People
- Jim Klostergaard
Organizations
- The University of Texas MD Anderson Cancer Center