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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 9, 2007 Accepted July 19, 2008 Effective dasatinib uptake may occur without human organic Cation Transporter 1 (hOCT1): implications for the treatment of imatinib resistant chronic myeloid leukaemia Athina Giannoudis, Andrea Davies, Claire M Lucas, Robert J Harris, Munir Pirmohamed, and Richard E Clark* Department of Haematology, University of Liverpool, Medical School, Liverpool, United Kingdom Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom * Corresponding author; email: clarkre{at}liverpool.ac.uk. We have previously shown that imatinib uptake into chronic myeloid leukaemia (CML) cells is dependent on human Organic Cation Transporter 1 (hOCT1; SLCA22), and that low hOCT1 expression is an important determinant of clinical outcome to imatinib treatment. We hypothesised that dasatinib might be transported differently to imatinib, possibly accounting for its favourable 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=0.02). However, hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells, in contrast to their block on imatinib uptake. Dasatinib decreased the level of phosphorylated CrkL to 49.9% in control and 40.3% in high-hOCT1 expressing cells. Dasatinib 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 by using the ABCB1 inhibitor PSC833 (p=0.001 and p<0.0001 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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