Synergistic antitumor activity of troxacitabine and camptothecin in selected human cancer cell lines.
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.
Kim
Tracy E
TE
Yale Cancer Center, Medical Oncology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Park
Shin-Young
SY
Hsu
Chih-Hung
CH
Dutschman
Ginger E
GE
Cheng
Yung-Chi
YC
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004148:Dioxolanes / Q000378:metabolism / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007624:KB Cells; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine; D003842:Deoxycytidine Kinase; D002166:Camptothecin