Analyses of the combination of 6-MP and dasatinib in cell culture

Kaur,Gurmeet; Behrsing,Holger; Parchment,Ralph  E.; Millin,Myrtle  Davis; Teicher,Beverly  A.

doi:10.3892/ijo.2013.1930

Analyses of the combination of 6-MP and dasatinib in cell culture

Authors:
- Gurmeet Kaur
- Holger Behrsing
- Ralph E. Parchment
- Myrtle Davis Millin
- Beverly A. Teicher
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Affiliations: Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA, Laboratory for Investigative Toxicology, Applied/Developmental Research Directorate, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA, Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20852, USA, Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20852, USA
Published online on: May 2, 2013 https://doi.org/10.3892/ijo.2013.1930
Pages: 13-22
Copyright: © Kaur et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

A major tenet of cancer therapeutics is that combinations of anticancer agents with different mechanisms of action and different toxicities may be effective treatment regimens. Evaluation of additivity/synergy in cell culture may be used to identify drug combination opportunities and to assess risk of additive/synergistic toxicity. The combination of 6-mercaptopurine and dasatinib was assessed for additivity/synergy using the combination index (CI) method and a response surface method in six human tumor cell lines including MCF-7 and MDA-MB‑468 breast cancer, NCI-H23 and NCI-H460 non‑small cell lung cancer, and A498 and 786-O renal cell cancer, based on two experimental end‑points: ATP content and colony formation. Clonal colony formation by human bone marrow CFU-GM was used to assess risk of enhanced toxicity. The concentration ranges tested for each drug were selected to encompass the clinical Cmax concentrations. The combination regimens were found to be additive to sub‑additive by both methods of data analysis, but synergy was not detected. The non-small cell lung cancer cell lines were the most responsive among the tumor lines tested and the renal cell carcinoma lines were the least responsive. The bone marrows CFU-GM were more sensitive to the combination regimens than were the tumor cell lines. Based upon these data, it appears that the possibility of enhanced efficacy from combining 6-mercaptopurine (6-MP) and dasatinib would be associated with increased risk of severe bone marrow toxicity, so the combination is unlikely to provide a therapeutic advantage for treating solid tumor patients where adequate bone marrow function must be preserved.

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