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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2501-2506. Prepublished online as a Blood First Edition Paper on November 15, 2005; DOI 10.1182/blood-2005-07-2966. This Article Full Text (PDF) All Versions of this Article: 2005-07-2966v1 107/6/2501    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 Chandra, J. Articles by Kaufmann, S. H Search for Related Content PubMed PubMed Citation Articles by Chandra, J. Articles by Kaufmann, S. H Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 26, 2005 Accepted November 1, 2005 Adaphostin-induced oxidative stress overcomes bcr/abl mutation-dependent and -independent imatinib resistance Joya Chandra*, Jeannette Tracy, David Loegering, Karen Flatten, Srdan Verstovsek, Miloslav Beran, Mercedes Gorre, Zeev Estrov, Nicholas Donato, Moshe Talpaz, Charles Sawyers, Kapil Bhalla, Judith Karp, Edward Sausville, and Scott H Kaufmann Department of Pediatrics Research, M.D. Anderson Cancer Center, Houston, TX, USA Division of Oncology Research and Hematology, Mayo Clinic, Rochester, MN, USA Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, USA Department of Hematology-Oncology, UCLA, Los Angeles, CA, USA Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA Department of Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA * Corresponding author; email: jchandra{at}mdanderson.org. The bcr/abl kinase has been targeted for the treatment of chronic myelogenous leukemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML and Ph+ ALL are often resistant. In particular, mutation of the T315 residue in the bcr/abl activation loop renders cells highly resistant to imatinib and to second-generation kinase inhibitors such as BMS354825 or AMN107. Adaphostin is a tyrphostin that was originally intended to inhibit the bcr/abl kinase by competing with its peptide substrates. Recent findings have, in addition, implicated the capacity to generate reactive oxygen species (ROS) in the cytotoxic mechanism of adaphostin. In view of this unique mode of action, we examined the effects of adaphostin on numerous imatinib-resistant leukemia models, including imatinib-resistant CML and Ph+ ALL cell lines, cells harboring point mutations in bcr/abl, and specimens from imatinib-resistant CML patients, using assays for intracellular ROS, apoptosis and clonogenicity. Every cell line model of imatinib resistance examined remained fully sensitive to adaphostin-induced cell death. Collectively, these data suggest that ROS generation by adaphostin overcomes even the most potent imatinib resistance in CML and Ph+ ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: ROS: double-edged sword for leukemic cells Neil E. Kay Blood 2006 107: 2212-2213. [Full Text] [PDF] This article has been cited by other articles: J. Zhang, M. Sattler, G. Tonon, C. Grabher, S. Lababidi, A. Zimmerhackl, M. S. Raab, S. Vallet, Y. Zhou, M.-A. Cartron, et al. 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