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Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-04-1074. This Article Full Text (PDF) All Versions of this Article: 2003-04-1074v1 103/1/208    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 La Rosee, P. Articles by Druker, B. J Search for Related Content PubMed PubMed Citation Articles by La Rosee, P. Articles by Druker, B. J Social Bookmarking                   What's this? Submitted April 7, 2003 Accepted August 12, 2003 In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl positive cell lines Paul La Rosee, Kara Johnson, Amie S Corbin, Eric P Stoffregen, Erika M Moseson, Stephanie Willis, Michael M Mauro, Junia V Melo, Michael W Deininger, and Brian J Druker* Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, OR, USA; III. Medizinische Universitaetsklinik, Fakultaet fur klinische Medizin Mannheim der Universitaet Heidelberg, Mannheim, Germany Department of Hematology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom Howard Hughes Medical Institute, Chevy Chase, MD, USA * Corresponding author; email: drukerb{at}ohsu.edu. Imatinib mesylate (GleevecTM, formerly STI571) is an effective therapy for all stages of chronic myelogenous leukemia (CML). While responses in chronic phase CML are generally durable, resistance develops in many patients with advanced disease. We evaluated novel antileukemic agents for their potential to overcome resistance in various imatinib-resistant cell lines. Using cell proliferation assays, we investigated whether different mechanisms of resistance to imatinib would alter the efficacy of arsenic trioxide (As2O3) or 5-Aza-2-deoxycytidine (decitabine) alone and in combination with imatinib. Our results indicate that resistance to imatinib induced by Bcr-Abl over-expression or by engineered expression of clinically relevant Bcr-Abl mutants does not induce cross-resistance to As2O3 or decitabine. Combined treatment with these agents and imatinib is beneficial in cell lines that have residual sensitivity to imatinib monotherapy, with synergistic growth inhibition achieved only at doses of imatinib that overcome resistance. In some imatinib-resistant cell lines, combination treatments that use low doses of imatinib lead to antagonism. Apoptosis studies suggest that this can be explained in part by the reduced pro-apoptotic activity of imatinib in resistant cell lines. This data underlines the importance of resistance-testing and provides a rational approach for dose adjusted administration of imatinib when combined with other agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. V. Melo and C. Chuah Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond Hematology, January 1, 2008; 2008(1): 427 - 435. [Abstract] [Full Text] [PDF] T. Qin, E. M. Youssef, J. Jelinek, R. Chen, A. S. Yang, G. Garcia-Manero, and J.-P. J. Issa Effect of Cytarabine and Decitabine in Combination in Human Leukemic Cell Lines Clin. Cancer Res., July 15, 2007; 13(14): 4225 - 4232. [Abstract] [Full Text] [PDF] H. Konig, N. Hartel, B. 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