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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1443-1452. Prepublished online as a Blood First Edition Paper on June 12, 2008; DOI 10.1182/blood-2007-11-123984. This Article Full Text (PDF) Supplemental Methods and Figure All Versions of this Article: blood-2007-11-123984v1 112/4/1443    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 Veldurthy, A. Articles by Krause, G. Search for Related Content PubMed PubMed Citation Articles by Veldurthy, A. Articles by Krause, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 29, 2007 Accepted May 28, 2008 The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes Aditya Veldurthy, Michaela Patz, Susanne Hagist, Christian P. Pallasch, Clemens-Martin Wendtner, Michael Hallek, and Gunter Krause* Department I for Internal Medicine, University Hospital Cologne, Cologne, Germany * Corresponding author; email: guenter.krause{at}uk-koeln.de. Src family kinases (SFKs) were described to be overexpressed in chronic lymphocytic leukemia (CLL). Therefore, we wished to examine the effects of the Src and Abl kinase inhibitor dasatinib on the intracellular signaling and survival of CLL cells. Dasatinib showed a dose and time dependent reduction of global tyrosine phosphorylation and of activating phosphotyrosine levels of SFKs. Treatment with 100 nM dasatinib led to decreased levels of the activated, phosphorylated forms of Akt, Erk1/2 and p38, and induced PARP cleavage through caspase activity. In Mec1 and JVM-3 cell lines, dasatinib increased p53 protein levels and inhibited proliferation. In freshly isolated CLL cells, dasatinib reduced the expression of Mcl-1 and Bcl-xL. Combination of 5 µM dasatinib and fludarabine increased the apoptosis induction of each by ~50 %. In 15 primary CLL samples, cells with unmutated immunoglobulin variable heavy chain (IgVH) genes were more sensitive to dasatinib than those with mutated IgVH genes (p=0.002). In summary, dasatinib shows potent inhibitory effects on the survival of CLL cells in vitro most prominently in samples obtained from patients with unfavorable prognostic features. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. M. Schrage, I. H. Briaire-de Bruijn, N. F.C.C. de Miranda, J. van Oosterwijk, A. H.M. Taminiau, T. van Wezel, P. C.W. Hogendoorn, and J. V.M.G. Bovee Kinome Profiling of Chondrosarcoma Reveals Src-Pathway Activity and Dasatinib as Option for Treatment Cancer Res., August 1, 2009; 69(15): 6216 - 6222. [Abstract] [Full Text] [PDF] M. Buchner, S. Fuchs, G. Prinz, D. Pfeifer, K. Bartholome, M. Burger, N. Chevalier, L. Vallat, J. Timmer, J. G. Gribben, et al. Spleen Tyrosine Kinase Is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia Cancer Res., July 1, 2009; 69(13): 5424 - 5432. [Abstract] [Full Text] [PDF] V. Pitini, C. Arrigo, and G. Altavilla Dasatinib induces a response in chronic lymphocytic leukemia Blood, January 8, 2009; 113(2): 498 - 498. [Full Text] [PDF]

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