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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3494-3503. Prepublished online as a Blood First Edition Paper on July 25, 2006; DOI 10.1182/blood-2006-04-015487. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-015487v1 108/10/3494    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 Knapper, S. Articles by Burnett, A. K Search for Related Content PubMed PubMed Citation Articles by Knapper, S. Articles by Burnett, A. K Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 13, 2006 Accepted June 28, 2006 The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3 mutated and wild type cases Steven Knapper*, Kenneth I Mills, Amanda F Gilkes, Steve J Austin, Val Walsh, and Alan K Burnett Department of Haematology, Cardiff University School of Medicine, Cardiff, Wales, United Kingdom * Corresponding author; email: knappers{at}cardiff.ac.uk. The receptor tyrosine kinase FLT3 is a promising molecular therapeutic target in AML. Activating mutations of FLT3 are present in approximately one-third of patients, while many non-mutants show evidence of FLT3 activation, which appears to play a significant role in leukemogenesis. We studied the effects of lestaurtinib (CEP701) and PKC412, two small molecule inhibitors of FLT3, on 65 diagnostic AML blast samples. Both agents induced concentration-dependent cytotoxicity in the majority of cases, although responses to PKC412 required higher drug concentrations. Cytotoxic responses were highly heterogeneous, and were only weakly associated with FLT3 mutation status and FLT3 expression. Importantly, lestaurtinib induced cytotoxicity in a synergistic fashion with cytarabine, particularly in FLT3 mutant samples. Both lestaurtinib and PKC412 caused inhibition of FLT3 phosphorylation in all samples. Translation of FLT3 inhibition into cytotoxicity was influenced by the degree of residual FLT3 phosphorylation remaining, and correlated with deactivation of STAT5 and MAP-kinase. FLT3 mutant and wild type cases both varied considerably in their dependence on FLT3 signaling for survival. These findings support the continued clinical assessment of FLT3 inhibitors in combination with cytotoxic chemotherapy: entry to future clinical trials should include FLT3 wild type patients and should remain unrestricted by FLT3 expression level. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Nishioka, T. Ikezoe, J. Yang, A. Miwa, T. Tasaka, Y. Kuwayama, K. Togitani, H. P. Koeffler, and A. Yokoyama Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo Blood, May 15, 2008; 111(10): 5086 - 5092. [Abstract] [Full Text] [PDF] R. E. Gale, C. Green, C. Allen, A. J. Mead, A. K. Burnett, R. K. Hills, D. C. Linch, and on behalf of the Medical Research Council Adult Le The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia Blood, March 1, 2008; 111(5): 2776 - 2784. [Abstract] [Full Text] [PDF] R. Skoda The Genetic Basis of Myeloproliferative Disorders Hematology, January 1, 2007; 2007(1): 1 - 10. [Abstract] [Full Text] [PDF]

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