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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 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 Citation Map 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 Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Active transport of imatinib into and out of cells: implications for drug resistance Julia Thomas, Lihui Wang, Richard E. Clark, and Munir Pirmohamed From the Department of Pharmacology and Therapeutics, University of Liverpool; and the Department of Haematology, University of Liverpool, Royal Liverpool University Hospital, United Kingdom. Imatinib is a tyrosine kinase inhibitor that is effective in the treatment of chronic myeloid leukemia (CML). Not all patients achieve cytogenetic response. Some patients even lose the 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 CCRFCEM and its drug-resistant subline VBL100 to measure the uptake of carbon 14 (14C)-labeled 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, whereas the inhibition of hOCT2 or hOCT3 had no effect, indicating that 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 the 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: D. K. Hiwase, V. Saunders, D. Hewett, A. Frede, S. Zrim, P. Dang, L. Eadie, L. B. To, J. Melo, S. Kumar, et al. Dasatinib Cellular Uptake and Efflux in Chronic Myeloid Leukemia Cells: Therapeutic Implications Clin. Cancer Res., June 15, 2008; 14(12): 3881 - 3888. [Abstract] [Full Text] [PDF] S. Hu, R. M. Franke, K. K. Filipski, C. Hu, S. J. Orwick, E. A. de Bruijn, H. Burger, S. D. Baker, and A. Sparreboom Interaction of Imatinib with Human Organic Ion Carriers Clin. 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[Abstract] [Full Text] [PDF] M. Puttini, A. M. L. Coluccia, F. Boschelli, L. Cleris, E. Marchesi, A. Donella-Deana, S. Ahmed, S. Redaelli, R. Piazza, V. Magistroni, et al. In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells Cancer Res., December 1, 2006; 66(23): 11314 - 11322. [Abstract] [Full Text] [PDF] D. Frame Chronic myeloid leukemia: Standard treatment options. Am. J. Health Syst. Pharm., December 1, 2006; 63(23_Supplement_8): S10 - S14. [Abstract] [Full Text] [PDF] P. La Rosee, T. Jia, S. Demehri, N. Hartel, P. de Vries, L. Bonham, D. Hollenback, J. W. Singer, J. V. Melo, B. J. Druker, et al. Antileukemic Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitor CT32228 in Chronic Myelogenous Leukemia Sensitive and Resistant to Imatinib. Clin. Cancer Res., November 1, 2006; 12(21): 6540 - 6546. [Abstract] [Full Text] [PDF] M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. 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Blood, August 15, 2006; 108(4): 1116 - 1117. [Full Text] [PDF] N. E. Jordanides, H. G. Jorgensen, T. L. Holyoake, and J. C. Mountford Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate Blood, August 15, 2006; 108(4): 1370 - 1373. [Abstract] [Full Text] [PDF] D. L. White, V. A. Saunders, P. Dang, J. Engler, A. C. W. Zannettino, A. C. Cambareri, S. R. Quinn, P. W. Manley, and T. P. Hughes OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib Blood, July 15, 2006; 108(2): 697 - 704. [Abstract] [Full Text] [PDF] M. Copland, A. Hamilton, L. J. Elrick, J. W. Baird, E. K. Allan, N. Jordanides, M. Barow, J. C. Mountford, and T. L. 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