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Spotlight on IMATINIB as a Model for Signal Transduction Inhibitors

Effect of imatinib on haematopoietic recovery following idarubicin exposure

Abstract

SCF is a potent pro-proliferative cytokine crucial for haematopoiesis, which binds to c-kit and activates its tyrosine kinase activity. Inactivating mutations of either SCF or c-kit have been described in mice and lead to increased sensitivity to treatment with ionising radiation. Imatinib is a tyrosine kinase inhibitor with high affinity for c-Abl, PDGFR and c-kit. In this study we investigated the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. Our results indicate that the simultaneous administration of imatinib enhances idarubicin-induced haematopoietic toxicity in vivo and in vitro.

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Acknowledgements

The authors thank Dr C Carlo-Stella, National Cancer Institute, for murine recombinant SCF and Dr P Dalerba, National Cancer Institute, for murine, recombinant IL-6. We are grateful to Dr E Buchdunger, Novartis Switzerland, for critical discussion and Dr R Gunby, National Cancer Institute, for kindly reviewing the manuscript. This work has been supported by the Italian Association for Cancer Research (AIRC), the Italian Ministry of Health (Ricerca Finalizzata) and MIUR-COFIN2001. HR is the recipient of a Marie-Curie individual fellowship (QLK3-CT-1999-51065) under the EC-5th framework program.

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Ruchatz, H., Puttini, M., Cleris, L. et al. Effect of imatinib on haematopoietic recovery following idarubicin exposure. Leukemia 17, 298–304 (2003). https://doi.org/10.1038/sj.leu.2402800

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