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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4064-4072. Prepublished online as a Blood First Edition Paper on August 30, 2007; DOI 10.1182/blood-2007-06-093617. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-06-093617v1 110/12/4064    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. Search for Related Content PubMed PubMed Citation Articles by White, D. L. Articles by Hughes, T. Related Collections Neoplasia Oncogenes and Tumor Suppressors Gene Expression Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity Deborah L. White1,2, Verity A. Saunders1, Phuong Dang1, Jane Engler1,2, Amity Venables1, Stephanie Zrim1, Andrew Zannettino1,2, Kevin Lynch3, Paul W. Manley4, and Timothy Hughes1,2,5 1 Division of Haematology, Institute of Medical and Veterinary Science (IMVS) and Hanson Institute, Adelaide, Australia; 2 Department of Medicine, University of Adelaide, Adelaide, Australia; 3 Novartis Oncology, Novartis Pharmaceuticals, Sydney, Australia; 4 Novartis Pharmaceuticals, Novartis Institutes for Biomedical Research, Basel, Switzerland; and 5 Department of Haemotology, Royal Adelaide Hospital, Adelaide, Australia Interpatient variability in intracellular uptake and retention (IUR) of imatinib may be due to variable function of the OCT-1 influx pump. OCT-1 activity was measured in pretherapy blood from chronic myeloid leukemia (CML) patients by calculating the difference in IUR of [14C]-imatinib with and without OCT-1 inhibition. Of patients with higher than median (high) OCT-1 activity, 85% achieved major molecular response (MMR) by 24 months, versus 45% with no more than a median (low) OCT-1 activity. Assessing patients receiving 600 mg imatinib per day and those averaging fewer than 600 mg over 12 months of therapy revealed patients with high OCT-1 activity achieved excellent molecular response regardless of dose, whereas response of patients with low OCT-1 activity was highly dose dependent. Of patients with low OCT-1 activity who received fewer than 600 mg, 45% failed to achieve a 2-log reduction by 12 months, and 82% failed to achieve a MMR by 18 months, compared with 8% and 17% in the cohort with high OCT-1 activity and dose less than 600 mg/day (P = .017 and P = .022). OCT-1 activity is an important determinant of molecular response to imatinib, with predictive value closely linked to dose. This pretherapy assay identifies patients at greatest risk of suboptimal response where dose intensity is critical, and those likely to respond equally well to standard dose imatinib. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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] R. A. Larson, B. J. Druker, F. Guilhot, S. G. O'Brien, G. J. Riviere, T. Krahnke, I. Gathmann, Y. Wang, and for the IRIS (International Randomized Interferon Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study Blood, April 15, 2008; 111(8): 4022 - 4028. [Abstract] [Full Text] [PDF] J. E. Cortes Imatinib and Beyond--Therapy of CML in 2008 ASCO Educational Book, January 1, 2008; 2008(1): 307 - 312. [Abstract] [Full Text] [PDF] G. Saglio, F. Pane, and G. Martinelli State-of-the-art Monitoring for Patients with Chronic Myeloid Leukemia ASCO Educational Book, January 1, 2008; 2008(1): 313 - 317. [Abstract] [Full Text] [PDF]

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