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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3739-3745. Prepublished online as a Blood First Edition Paper on August 17, 2004; DOI 10.1182/blood-2003-12-4276. This Article Full Text (PDF) All Versions of this Article: 2003-12-4276v1 104/12/3739    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Thomas, J. Articles by Pirmohamed, M. Search for Related Content PubMed PubMed Citation Articles by Thomas, J. Articles by Pirmohamed, M. Related Collections Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 19, 2003 Accepted July 25, 2004 Active Transport of Imatinib into and Out of Cells: Implications for Drug Resistance Julia Thomas, Lihui Wang, Richard E Clark, and Munir Pirmohamed* Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, United Kingdom Department of Haematology, Royal Liverpool University Hospital, Liverpool, United Kingdom * Corresponding author; email: munirp{at}liv.ac.uk. Imatinib is a tyrosine kinase inhibitor that is effective in the treatment of chronic myeloid leukemia. Not all patients achieve a cytogenetic response, while other patients lose an initial cytogenetic response. In this study, we investigated the active cellular transport of imatinib to gain a better understanding of the possible mechanisms of imatinib resistance. We used the leukemic cell line CCRF-CEM and its drug resistant sub-line VBL100 to measure the uptake of 14C-labelled imatinib. Imatinib uptake was temperature-dependent, indicative of an active uptake process. Additionally, incubations with transport inhibitors showed that verapamil, amantadine and procainamide, inhibitors of the human organic cation transporter 1 (hOCT1) significantly decreased imatinib uptake into CEM cells, while inhibition of hOCT2 or hOCT3 had no effect, indicating influx into the cells is an active process likely to be mediated by hOCT1. Studies using transfected MDCK cell lines revealed an active efflux component attributable to MDR1 (ABCB1). Both hOCT1 and MDR1 were expressed in CML primary cells and cell lines. The results indicate that active transport processes mediate both influx and efflux of imatinib. Differential expression of influx (hOCT1) and efflux (MDR1) transporters may be a critical determinant of intracellular drug levels, and hence resistance to imatinib. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: hOCT 1 and resistance to imatinib Lucy C. Crossman, Brian J. Druker, Michael W. N. Deininger, Munir Pirmohamed, Lihui Wang, and Richard E. Clark Blood 2005 106: 1133-1134. [Full Text] [PDF] This article has been cited by other articles: C. M. Lucas, R. J. Harris, A. Giannoudis, A. Davies, K. Knight, S. J. Watmough, L. Wang, and R. E. Clark Chronic myeloid leukemia patients with the e13a2 BCR-ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript Haematologica, October 1, 2009; 94(10): 1362 - 1367. [Abstract] [Full Text] [PDF] S. Hu, Z. Chen, R. Franke, S. Orwick, M. Zhao, M. A. Rudek, A. Sparreboom, and S. D. 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Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study Blood, October 1, 2007; 110(7): 2309 - 2315. [Abstract] [Full Text] [PDF] F. Guilhot, J. Apperley, D.-W. Kim, E. O. Bullorsky, M. Baccarani, G. J. Roboz, S. Amadori, C. A. de Souza, J. H. Lipton, A. Hochhaus, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase Blood, May 15, 2007; 109(10): 4143 - 4150. [Abstract] [Full Text] [PDF] A. Hochhaus, H. M. Kantarjian, M. Baccarani, J. H. Lipton, J. F. Apperley, B. J. Druker, T. Facon, S. L. Goldberg, F. Cervantes, D. Niederwieser, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy Blood, March 15, 2007; 109(6): 2303 - 2309. [Abstract] [Full Text] [PDF] Y. Wang, D. Cai, C. Brendel, C. Barett, P. Erben, P. W. Manley, A. Hochhaus, A. Neubauer, and A. Burchert Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation Blood, March 1, 2007; 109(5): 2147 - 2155. [Abstract] [Full Text] [PDF] D. A. Thomas Philadelphia Chromosome Positive Acute Lymphocytic Leukemia: A New Era of Challenges Hematology, January 1, 2007; 2007(1): 435 - 443. [Abstract] [Full Text] [PDF] H. M. Kantarjian, M. Talpaz, F. Giles, S. O'Brien, and J. Cortes New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance Ann Intern Med, December 19, 2006; 145(12): 913 - 923. [Abstract] [Full Text] [PDF] B. J. 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