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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1366-1377. Prepublished online as a Blood First Edition Paper on October 25, 2007; DOI 10.1182/blood-2007-04-084814. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-04-084814v1 111/3/1366    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 Schade, A. E. Articles by Maciejewski, J. P. Search for Related Content PubMed PubMed Citation Articles by Schade, A. E. Articles by Maciejewski, J. P. Related Collections Immunobiology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation Andrew E. Schade1,2, Gary L. Schieven3, Robert Townsend3, Anna M. Jankowska1, Vojkan Susulic3, Rosemary Zhang3, Hadrian Szpurka1, and Jaroslaw P. Maciejewski1 1 Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center and 2 Department of Clinical Pathology, Cleveland Clinic Foundation, OH; and 3 Immunology Drug Discovery, Bristol-Myers Squibb Research and Development, Princeton, NJ Dasatinib is an oral small molecule inhibitor of Abl and Src family tyrosine kinases (SFK), including p56Lck (Lck). Given the central importance of Lck in transmitting signals from the T-cell receptor (TCR) signaling complex and the potent ability of dasatinib to inhibit Lck activity, we hypothesized this agent could provide a novel route of immunomodulation via targeted inhibition of antigen-induced signaling. Herein, we show that dasatinib inhibits TCR-mediated signal transduction, cellular proliferation, cytokine production, and in vivo T-cell responses. However, dasatinib-mediated inhibition does not induce apoptosis because the effect is reversible or may be overcome by signals bypassing the TCR, such as phorbol ester. Signal transduction and proliferative responses via IL-2 remain essentially unperturbed, suggesting that dasatinib displays specificity for TCR signaling. In addition, dasatinib combined with cyclosporine A or rapamycin led to a much more potent inhibition of T-cell activation, suggesting that targeted inhibition of Lck could be a useful adjunct for enhanced immunomodulation. In combination with currently available immunomodulatory agents, SFK inhibition could potentially increase immunomodulatory efficacy while minimizing toxicity of individual agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Dasatinib suppresses in vitro natural killer cell cytotoxicity Stephen J. Blake, A. Bruce Lyons, Cara K. Fraser, John D. Hayball, and Timothy P. Hughes Blood 2008 111: 4415-4416. [Full Text] [PDF] This article has been cited by other articles: R. A. Wilcox, D. A. Wada, S. C. Ziesmer, S. F. Elsawa, N. I. Comfere, A. B. Dietz, A. J. Novak, T. E. Witzig, A. L. Feldman, M. R. Pittelkow, et al. Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells Blood, October 1, 2009; 114(14): 2936 - 2944. [Abstract] [Full Text] [PDF] M. T. Voso, V. Santini, C. Finelli, P. Musto, E. Pogliani, E. Angelucci, G. Fioritoni, G. Alimena, L. Maurillo, A. Cortelezzi, et al. Valproic Acid at Therapeutic Plasma Levels May Increase 5-Azacytidine Efficacy in Higher Risk Myelodysplastic Syndromes Clin. Cancer Res., August 1, 2009; 15(15): 5002 - 5007. [Abstract] [Full Text] [PDF] M. Brehme, O. Hantschel, J. Colinge, I. Kaupe, M. Planyavsky, T. Kocher, K. Mechtler, K. L. Bennett, and G. Superti-Furga Charting the molecular network of the drug target Bcr-Abl PNAS, May 5, 2009; 106(18): 7414 - 7419. [Abstract] [Full Text] [PDF] D. H. Kim, S. Kamel-Reid, H. Chang, R. Sutherland, C. W. Jung, H.-J. Kim, J.-J. Lee, and J. H. Lipton Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia Haematologica, January 1, 2009; 94(1): 135 - 139. [Abstract] [Full Text] [PDF] D. Y. H. Hallaert, A. Jaspers, C. J. van Noesel, M. H. J. van Oers, A. P. Kater, and E. Eldering c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches Blood, December 15, 2008; 112(13): 5141 - 5149. [Abstract] [Full Text] [PDF] S. J. Blake, A. Bruce Lyons, C. K. Fraser, J. D. Hayball, and T. P. Hughes Dasatinib suppresses in vitro natural killer cell cytotoxicity Blood, April 15, 2008; 111(8): 4415 - 4416. [Full Text] [PDF] M. Kneidinger, U. Schmidt, U. Rix, K. V. Gleixner, A. Vales, C. Baumgartner, C. Lupinek, M. Weghofer, K. L. Bennett, H. Herrmann, et al. The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils Blood, March 15, 2008; 111(6): 3097 - 3107. [Abstract] [Full Text] [PDF]

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