TLK286, a novel glutathione analog prodrug, induces resensitization to carboplatin in human ovarian cancer, OVCAR3, platinum resistant cells
Zhuo Wang, James G. Keck, Gail L. Brown, Hua Xu. Telik, Inc., Palo Alto, CA.
The development of resistance to platinum drugs has limited their efficacy and is an important clinical problem. The mechanisms of resistance appear to be multifactorial, including changes in cellular metabolism affecting the regulation of cell division and death, decreased drug uptake and increased drug efflux.
A Phase 2 study of the combination of TLK286, a novel glutathione analog prodrug, with carboplatin in platinum refractory or resistant ovarian cancer patients showed a 54% objective response rate, including complete responses, suggesting that TLK286 has the ability to resensitize ovarian cancer cells to carboplatin.
To better understand the molecular mechanism of resensitization we have developed, using increasing concentrations of carboplatin, a platinum resistant derivative of the OVCAR3 human ovarian cancer cell line (OVCAR3R) as an in vitro model system.
The OVCAR3R cells displayed approximately 5 fold resistance to carboplatin and did not demonstrate cross-resistance to TLK286. Interestingly, drug combination studies as analyzed by the Combination Index (CI) method, where a value below 1.0 indicates synergy, revealed that the synergy between TLK286 and carboplatin was greater in the carboplatin-resistant cells (CI = 0.75) than in the platinum sensitive parental cells (CI=0.90), consistent with resensitization of the cell line to carboplatin.
Studies are currently underway to further characterize the carboplatin resistant cell line and the mechanism of resensitization to carboplatin, including effects on cellular drug-related metabolic enzymes.
AACR 2005 Abstract #1500
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