PT  - JOURNAL ARTICLE
AU  - Kim, Tracy E.
AU  - Park, Shin-Young
AU  - Hsu, Chih-Hung
AU  - Dutschman, Ginger E.
AU  - Cheng, Yung-Chi
TI  - Synergistic Antitumor Activity of Troxacitabine and Camptothecin in Selected Human Cancer Cell Lines
AID  - 10.1124/mol.66.2.285
DP  - 2004 Aug 01
TA  - Molecular Pharmacology
PG  - 285--292
VI  - 66
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/66/2/285.short
4100  - http://molpharm.aspetjournals.org/content/66/2/285.full
SO  - Mol Pharmacol2004 Aug 01; 66
AB  - 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.