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Blood, 15 July 2006, Vol. 108, No. 2, pp. 697-704. Prepublished online as a Blood First Edition Paper on April 4, 2006; DOI 10.1182/blood-2005-11-4687. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-11-4687v1 108/2/697    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 White, D. L. Articles by Hughes, T. P. Search for Related Content PubMed PubMed Citation Articles by White, D. L. Articles by Hughes, T. P. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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 Deborah L. White, Verity A. Saunders, Phuong Dang, Jane Engler, Andrew C. W. Zannettino, Antony C. Cambareri, Steven R. Quinn, Paul W. Manley, and Timothy P. Hughes From the Division of Hematology, Institute of Medical and Veterinary Science (IMVS) & Hanson Institute, Adelaide, South Australia, Australia; Novartis Pharmaceuticals, Sydney, Australia; Novartis Institutes for Biomedical Research, Basel, Switzerland; and the University of Adelaide, Australia. Intrinsic sensitivity of newly diagnosed chronic myeloid leukemia (CML) patients to imatinib (IC50imatinib) correlates with molecular response. IC50imatinib is defined as the in vitro concentration of drug required to reduce phosphorylation of the adaptor protein Crkl by 50%. We now show that interpatient variability in IC50imatinib is mainly due to differences in the efficiency of imatinib intracellular uptake and retention (IUR). In 25 untreated CML patients, the IC50imatinib strongly correlated (R 2 = –0.484, P = .014 at 2 µM imatinib) with the IUR of [14C]imatinib. The addition of prazosin, a potent inhibitor of OCT-1 cellular transporter, reduced the IUR and eliminated interpatient variability. IC50 values for the more potent BCR-ABL inhibitor nilotinib (AMN107) did not correlate with IC50imatinib (R2 =–0.0561, P > .05). There was also no correlation between IC50nilotinib and the IUR for [14C]nilotinib (R 2 = 0.457, P > .05). Prazosin had no effect on nilotinib IUR, suggesting that influx of nilotinib is not mediated by OCT-1. In conclusion, whereas OCT-1–mediated influx may be a key determinant of molecular response to imatinib, it is unlikely to impact on cellular uptake and patient response to nilotinib. Determining interpatient and interdrug differences in cellular uptake and retention could allow individual optimization of kinase inhibitor therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Wu, F. Meng, L.-Y. Kong, Z. Peng, Y. Ying, W. G. Bornmann, B. G. Darnay, B. Lamothe, H. Sun, M. Talpaz, et al. Association Between Imatinib-Resistant BCR-ABL Mutation-Negative Leukemia and Persistent Activation of LYN Kinase J Natl Cancer Inst, July 2, 2008; 100(13): 926 - 939. [Abstract] [Full Text] [PDF] 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. 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