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Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

Human ovarian carcinoma cells (C70 and C200) made resistant to cisplatin from A2780 cells demonstrated an 20-fold resistance to the drug. These same cell lines showed no collateral resistance (as compared with the wild-type) to a novel glutathione S-transferase -activated prodrug {-glutamyl--amino-ß[2-ethyl-N,N,N',N'-tetrakis (2-chloroethyl) phosphorodiamidate]-sulfonyl-propionyl-(R)-(-) phenylglycine; TLK286}. Previous results have shown a direct correlation between levels of GST expression and cytotoxicity for TLK286 (L. A. Rosario et al., Mol. Pharmacol., 58: 167–174, 2000.). However, protein levels of the isozyme were identical in wild-type C70 and C200 cell lines. In analyzing the DNA repair capacity of C70 and C200, an altered expression of the DNA-dependent protein kinase (DNA-PK) complex (catalytic subunit DNA-PKcs, and the heterodimers Ku70 and Ku80) was found. In C70 and C200 cells, DNA-PKcs was overexpressed at both the transcript and protein levels, whereas amounts of Ku70 and Ku80 were higher only at the level of protein expression. TLK286 in either its parent or activated form inhibited the catalytic kinase activity of purified DNA-PK with an IC₅₀ value of 1 µM. Coimmunoprecipitation of Ku70 after TLK286 treatment of purified DNA-PK and C70 cells showed a drug-induced destabilization of the protein-protein interaction between the catalytic subunit and the Ku heterodimer. Overall, these results implicate inhibition of DNA-PK as a component of TLK286 cytotoxicity and provide a rationale for its use in the clinical management of cisplatin-resistant ovarian cancer.

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