Abstract

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.