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Blood, 1 January 2004, Vol. 103, No. 1, pp. 208-215. Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-04-1074. This Article Full Text 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 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 La Rosée, P. Articles by Druker, B. J. Search for Related Content PubMed PubMed Citation Articles by La Rosée, P. Articles by Druker, B. J. Related Collections Apoptosis Oncogenes and Tumor Suppressors Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl–positive cell lines Paul La Rosée, 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 From the Oregon Health and Science University Cancer Institute, Division of Hematology and Medical Oncology, Portland, OR; 3 Medizinische Universitätsklinik, Fakultät für klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany; Department of Hematology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom; and Howard Hughes Medical Institute, Chevy Chase, MD. Imatinib mesylate (Gleevec, 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 overexpression 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 proapoptotic activity of imatinib in resistant cell lines. These data underline the importance of resistance testing and provide 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: 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. Schultheis, M. Schatz, C. Lorentz, J. V. Melo, R. Hehlmann, A. Hochhaus, and P. La Rosee Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide through glutathione-depletion in imatinib-resistant cells Haematologica, June 1, 2007; 92(6): 838 - 841. [Abstract] [Full Text] [PDF] P. Yoon, N. Giafis, J. Smith, H. Mears, E. Katsoulidis, A. Sassano, J. Altman, A. J. Redig, M. S. Tallman, and L. C. Platanias Activation of mammalian target of rapamycin and the p70 S6 kinase by arsenic trioxide in BCR-ABL-expressing cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2815 - 2823. [Abstract] [Full Text] [PDF] P. La Rosee, T. Jia, S. Demehri, N. Hartel, P. de Vries, L. Bonham, D. Hollenback, J. W. Singer, J. V. Melo, B. J. Druker, et al. Antileukemic Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitor CT32228 in Chronic Myelogenous Leukemia Sensitive and Resistant to Imatinib. Clin. Cancer Res., November 1, 2006; 12(21): 6540 - 6546. [Abstract] [Full Text] [PDF] M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF] L. McCallum, S. Price, N. Planque, B. Perbal, A. Pierce, A. D. Whetton, and A. E. Irvine A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation Blood, September 1, 2006; 108(5): 1716 - 1723. [Abstract] [Full Text] [PDF] J. Chandra, J. Tracy, D. Loegering, K. Flatten, S. Verstovsek, M. Beran, M. Gorre, Z. Estrov, N. Donato, M. 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