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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3348-3354. Prepublished online as a Blood First Edition Paper on July 31, 2008; DOI 10.1182/blood-2007-10-116236. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-10-116236v1 112/8/3348    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 Giannoudis, A. Articles by Clark, R. E. Search for Related Content PubMed PubMed Citation Articles by Giannoudis, A. Articles by Clark, R. E. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia Athina Giannoudis1, Andrea Davies1, Claire M. Lucas1, Robert J. Harris1, Munir Pirmohamed2, and Richard E. Clark1 1 Department of Haematology and 2 Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom We have previously shown that imatinib uptake into chronic myeloid leukemia (CML) cells is dependent on human organic cation transporter 1 (hOCT1; SLC22A1), and that low hOCT1 expression is an important determinant of clinical outcome to imatinib treatment. We hypothesized that dasatinib might be transported differently than imatinib, possibly accounting for its favorable effects in imatinib-resistant patients. 14C-dasatinib uptake was greater in KCL22-transfected cells with pcDNA3-hOCT1 plasmid (high hOCT1-expressing cells) than in control cells (P = .02). However, hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells, in contrast to their block on imatinib uptake. Dasa-tinib decreased the level of phosphorylated CrkL to 49.9% in control and 40.3% in high hOCT1-expressing cells. Dasa-tinib efflux was investigated in confluent ABCB1-transfected MDCKII cell monolayers. Both dasatinib and imatinib were transported from the basal to the apical layer, indicating that they were transported by ABCB1, which was confirmed using the ABCB1 inhibitor PSC833 (P = .001 and P < .001, respectively). Compared with imatinib, dasatinib achieved superior intracellular levels and BCR-ABL suppression even in cells with low or blocked hOCT1. Efflux of dasatinib and imatinib appear similar via ABCB1. Dasatinib may therefore offer an advantage over imatinib in patients with low hOCT1 expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. S. Lagas, R. A.B. van Waterschoot, V. A.C.J. van Tilburg, M. J. Hillebrand, N. Lankheet, H. Rosing, J. H. Beijnen, and A. H. Schinkel Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment Clin. Cancer Res., April 1, 2009; 15(7): 2344 - 2351. [Abstract] [Full Text] [PDF] K. He, M. W. Lago, R. A. Iyer, W.-C. Shyu, W. G. Humphreys, and L. J. Christopher Lacteal Secretion, Fetal and Maternal Tissue Distribution of Dasatinib in Rats Drug Metab. Dispos., December 1, 2008; 36(12): 2564 - 2570. [Abstract] [Full Text] [PDF]

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