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Synergistic Antitumor Activity of Troxacitabine and Camptothecin in Selected Human Cancer Cell Lines

Yale Cancer Center, Medical Oncology (T.E.K.) and Department of Pharmacology (S.-Y.P., C.-H.H., G.E.D., Y.-C.C.), Yale University School of Medicine, New Haven, Connecticut

Troxacitabine (L-OddC) is an L-configuration deoxycytidine analog currently in phase II trials for the treatment of cancer. The cytotoxicity of L-OddC in combination with other anticancer agents has not been studied systematically. In the present study, we assessed the cytotoxic effects produced by the combinations of L-OddC and several commonly used chemotherapy drugs in a panel of cultured human cancer cell lines. Growth inhibition resulting from simultaneous exposure to two-drug combinations was determined using the methylene blue staining method. Camptothecin (CPT) and analogs exhibited additives to synergistic interactions with L-OddC by isobologram analysis. These effects were cell type-specific, with the most pronounced synergism being observed in KB oropharyngeal carcinoma and CPT-resistant KB100 cell lines. In KB cells, the total cellular uptake and DNA incorporation of L-OddC were increased by the addition of CPT. One explanation that emerged from enzyme assays of deoxycytidine kinase (dCK) and deoxycytidine monophosphate kinase (dCMPK), key enzymes involved in L-OddC phosphorylation, was that CPT protected against L-OddC–induced reduction in dCK and dCMPK activity. The resulting increase in L-OddC metabolites and incorporation into DNA was associated with enhanced L-OddC cytotoxicity. These findings will be useful in designing future clinical trials of combination chemotherapy with L-OddC and CPT analogs with the potential for a broad use against both hematological and solid tumors.

Address correspondence to: Dr. Yung-Chi Cheng, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, SHM B226, New Haven, CT 06520. E-mail: cheng.lab{at}yale.edu