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P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate

Leukemia volume 18, pages 401–408 (2004)Cite this article

Abstract

Imatinib (Glivec®, STI571) is an intracellular acting drug that demonstrates high activity against BCR-ABL-positive chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). However, many patients, especially with advanced disease, develop drug resistance. Here, we show by a novel high-performance liquid chromatography-based method that intracellular levels of imatinib decrease in P-glycoprotein (Pgp)-positive leukemic cells. In a model of K562 cells with gradually increasing Pgp expression, a Pgp-dependent decline of intracellular imatinib levels was observed. Decreased imatinib levels were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of imatinib on cellular proliferation and apoptosis. The modulation of Pgp by cyclosporin A (CSA) readily restored imatinib cytotoxicity in these cells. Finally, we provide first data showing a biological effect of Pgp modulation in the imatinib treatment of a patient with BCR-ABL-positive ALL. MDR1 overexpression must therefore be considered as an important clinical mechanism in the diversity of resistance development to imatinib treatment.

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Acknowledgements

We are very grateful for the excellent technical assistance of Edith Harbig-Brutscher and Anja Liebkopf.

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Authors and Affiliations

  1. Medical Clinic and Policlinic I, University Hospital of the Technical University, Dresden, Germany

    T Illmer, M Schaich, U Platzbecker, J Freiberg-Richter, U Oelschlägel, M von Bonin, S Pursche, T Bergemann, G Ehninger & E Schleyer

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  1. T Illmer
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Correspondence to T Illmer.

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Illmer, T., Schaich, M., Platzbecker, U. et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 18, 401–408 (2004). https://doi.org/10.1038/sj.leu.2403257

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