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Research ArticleArticle

Synergistic Antitumor Activity of Troxacitabine and Camptothecin in Selected Human Cancer Cell Lines

Tracy E. Kim, Shin-Young Park, Chih-Hung Hsu, Ginger E. Dutschman and Yung-Chi Cheng
Molecular Pharmacology August 2004, 66 (2) 285-292; DOI: https://doi.org/10.1124/mol.66.2.285
Tracy E. Kim
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Shin-Young Park
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Chih-Hung Hsu
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Ginger E. Dutschman
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Yung-Chi Cheng
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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.

  • Received February 6, 2004.
  • Accepted April 23, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (2)
Molecular Pharmacology
Vol. 66, Issue 2
1 Aug 2004
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Research ArticleArticle

Synergistic Antitumor Activity of Troxacitabine and Camptothecin in Selected Human Cancer Cell Lines

Tracy E. Kim, Shin-Young Park, Chih-Hung Hsu, Ginger E. Dutschman and Yung-Chi Cheng
Molecular Pharmacology August 1, 2004, 66 (2) 285-292; DOI: https://doi.org/10.1124/mol.66.2.285

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Research ArticleArticle

Synergistic Antitumor Activity of Troxacitabine and Camptothecin in Selected Human Cancer Cell Lines

Tracy E. Kim, Shin-Young Park, Chih-Hung Hsu, Ginger E. Dutschman and Yung-Chi Cheng
Molecular Pharmacology August 1, 2004, 66 (2) 285-292; DOI: https://doi.org/10.1124/mol.66.2.285
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