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

Mol Pharmacol. 2004 Aug;66(2):285-92. doi: 10.1124/mol.66.2.285.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Camptothecin / pharmacology*
  • Cell Survival / drug effects
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • Cytosine / pharmacology*
  • DNA Damage / drug effects
  • Deoxycytidine Kinase / metabolism
  • Dioxolanes / metabolism
  • Dioxolanes / pharmacology*
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Humans
  • KB Cells
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Phytogenic
  • Dioxolanes
  • troxacitabine
  • Cytosine
  • Deoxycytidine Kinase
  • Camptothecin