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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 4, 2007 Accepted August 23, 2007 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 White*, Verity A Saunders, Phuong Dang, Jane Engler, Amity Venables, Stephanie Zrim, Andrew Zannettino, Kevin Lynch, Paul W Manley, and Timothy Hughes Division of Haematology, IMVS and Hanson Institute, Adelaide, South Australia, Australia Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia Novartis Oncology, Novartis Pharmaceuticals Pty Ltd., Sydney, NSW, Australia Novartis Institutes for Biomedical Research, Novartis Pharmaceutical, Basel, Switzerland Department of Haematology, Royal Adelaide Hospital, Adelaide, South Australia, Australia * Corresponding author; email: deb.white{at}imvs.sa.gov.au. 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 pre-therapy blood from CML patients by calculating the difference in IUR of [14C]-imatinib with and without OCT-1 inhibition. 85% of patients with >median (high) OCT-1 Activity achieved major molecular response (MMR) by 24 months, versus 45% with median (low) OCT-1 Activity. Assessing patients receiving 600mg imatinib/day and those averaging <600mg 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. 45% of patients with low OCT-1 Activity who received <600mg failed to achieve a 2 log reduction by 12 months, and 82% failed to achieve a MMR by 18 months, compared to 8% and 17% in the cohort with high OCT-1 Activity and dose <600 mg/day (p=0.017 and p=0.022). OCT-1 Activity is an important determinant of molecular response to imatinib, with predictive value closely linked to dose. This pre-therapy 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: W. W. Zhang, J. E. Cortes, H. Yao, L. Zhang, N. G. Reddy, E. Jabbour, H. M. Kantarjian, and D. Jones Predictors of Primary Imatinib Resistance in Chronic Myelogenous Leukemia Are Distinct From Those in Secondary Imatinib Resistance J. Clin. Oncol., August 1, 2009; 27(22): 3642 - 3649. [Abstract] [Full Text] [PDF] D. H. Kim, L. Sriharsha, W. Xu, S. Kamel-Reid, X. Liu, K. Siminovitch, H. A. Messner, and J. H. 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