Synergistic antitumor activity of troxacitabine and camptothecin in selected human cancer cell lines.

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Kim TE, Park SY, Hsu CH, Dutschman GE, Cheng YC

Synergistic antitumor activity of troxacitabine and camptothecin in selected human cancer cell lines.

Mol Pharmacol. 2004 Aug;66(2):285-92.

PubMed ID
15266019 [ View in PubMed
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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.

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