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Spotlight on IMATINIB as a Model for Signal Transduction Inhibitors

Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs

Leukemia volume 16, pages 2349–2357 (2002)Cite this article

Abstract

Imatinib mesylate (STI571, Glivec, Gleevec) is a powerful inhibitor of the tyrosine kinase activity of Bcr-Abl, the oncoprotein responsible for chronic myeloid leukemia (CML). The drug shows great efficacy in chronic phase, but is less effective in maintaining hematologic remissions in blast crisis patients. Our group has previously described several cell lines made resistant to imatinib. We now examine the question of cross-resistance to other chemotherapeutic drugs used in CML. Four paired imatinib-sensitive/resistant CML cell lines were assessed by caspase-3 and MTS assays for their proliferative response to cytosine arabinoside (Ara-C), daunorubicin (DNR), homoharringtonine (HHT) and hydroxyurea (HU), either alone or in combination with imatinib. Primary blasts from advanced-stage CML patients refractory to imatinib therapy were studied by semi-solid media clonogenic assays. We found that these drugs are generally capable of major inhibition of proliferation of the CML cell lines, although differential responses to DNR and HHT were noted between some sensitive and resistant cell line pairs, implying that resistance to imatinib may confer a growth advantage under such conditions. The four drugs were also effective in preventing the formation of progenitor cell colonies from CML patients both before treatment with imatinib, and after relapse on the drug. Isobolographic analysis implied that these drugs will generally combine well with imatinib, and in some cases will be synergistic. We conclude that Ara-C, DNR or HHT, either alone or in combination with imatinib, are likely to be the best therapeutic alternatives in the management of patients who become resistant to imatinib monotherapy.

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Acknowledgements

This work was supported by grants from the Leukaemia Research Fund, UK (AJT, GZ, JMG, JM) and the Association pour la recherche sur le cancer and Fondation de la recherche medicale, France (FXM, VL). We are grateful to Dr Elisabeth Buchdunger (Novartis Pharma, Basel, Switzerland) for providing imatinib mesylate, Dr Jean Pierre Robin (Oncopharm, Le Mans, France) for homoharringtonine, and Dr Richard Szydlo for help with the statistical analysis.

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Authors and Affiliations

  1. Dept of Haematology, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK

    AJ Tipping, G Zafirides, JM Goldman & JV Melo

  2. Laboratoire de Greffe de Moelle, Université Victor Segalen, Bordeaux, France

    FX Mahon & V Lagarde

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Tipping, A., Mahon, F., Zafirides, G. et al. Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. Leukemia 16, 2349–2357 (2002). https://doi.org/10.1038/sj.leu.2402775

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