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This Article Full Text Full Text (PDF) 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 Levis, M. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Levis, M. Articles by Small, D. Related Collections Hematopoiesis and Stem Cells Neoplasia Plenary Papers Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 June 2002, Vol. 99, No. 11, pp. 3885-3891 PLENARY PAPER A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo Mark Levis, Jeffrey Allebach, Kam-Fai Tse, Rui Zheng, Brenda R. Baldwin, B. Douglas Smith, Susan Jones-Bolin, Bruce Ruggeri, Craig Dionne, and Donald Small From Johns Hopkins University School of Medicine, Departments of Oncology and Pediatrics, Baltimore, MD; and Cephalon, West Chester, PA. Constitutively activating internal tandem duplication (ITD) and point mutations of the receptor tyrosine kinase FLT3 are present in up to 41% of patients with acute myeloid leukemia (AML). These FLT3/ITD mutations are likely to be important because their presence is associated with a poor prognosis. Both types of mutations appear to activate the tyrosine kinase activity of FLT3. We describe here the identification and characterization of the indolocarbazole derivative CEP-701 as a FLT3 inhibitor. This drug potently and selectively inhibits autophosphorylation of wild-type and constitutively activated mutant FLT3 in vitro in FLT3/ITD-transfected cells and in human FLT3-expressing myeloid leukemia-derived cell lines. We demonstrate that CEP-701 induces a cytotoxic effect on cells in a dose-responsive fashion that parallels the inhibition of FLT3. STAT5 and ERK1/2, downstream targets of FLT3 in the signaling pathway, are inhibited in response to FLT3 inhibition. In primary leukemia blasts from AML patients harboring FLT3/ITD mutations, FLT3 is also inhibited, with an associated cytotoxic response. Finally, using a mouse model of FLT3/ITD leukemia, we demonstrate that the drug inhibits FLT3 phosphorylation in vivo and prolongs survival. These findings form the basis for a planned clinical trial of CEP-701 in patients with AML harboring FLT3- activating mutations. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. E. Perl, M. T. Kasner, D. E. Tsai, D. T. Vogl, A. W. Loren, S. J. Schuster, D. L. Porter, E. A. Stadtmauer, S. C. Goldstein, N. V. Frey, et al. 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FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance Blood, October 1, 2003; 102(7): 2387 - 2394. [Abstract] [Full Text] [PDF] C. J. Strock, J.-I. Park, M. Rosen, C. Dionne, B. Ruggeri, S. Jones-Bolin, S. R. Denmeade, D. W. Ball, and B. D. Nelkin CEP-701 and CEP-751 Inhibit Constitutively Activated RET Tyrosine Kinase Activity and Block Medullary Thyroid Carcinoma Cell Growth Cancer Res., September 1, 2003; 63(17): 5559 - 5563. [Abstract] [Full Text] [PDF] K. Murata, H. Kumagai, T. Kawashima, K. Tamitsu, M. Irie, H. Nakajima, S. Suzu, M. Shibuya, S. Kamihira, T. Nosaka, et al. Selective Cytotoxic Mechanism of GTP-14564, a Novel Tyrosine Kinase Inhibitor in Leukemia Cells Expressing a Constitutively Active Fms-like Tyrosine Kinase 3 (FLT3) J. Biol. Chem., August 29, 2003; 278(35): 32892 - 32898. [Abstract] [Full Text] [PDF] J. H. Antin A 41-Year-Old Woman With Chronic Myelogenous Leukemia JAMA, August 27, 2003; 290(8): 1083 - 1090. [Full Text] [PDF] K. M. Murphy, M. Levis, M. J. Hafez, T. Geiger, L. C. Cooper, B.D. Smith, D. Small, and K. D. Berg Detection of FLT3 Internal Tandem Duplication and D835 Mutations by a Multiplex Polymerase Chain Reaction and Capillary Electrophoresis Assay J. Mol. Diagn., May 1, 2003; 5(2): 96 - 102. [Abstract] [Full Text] [PDF] A.-M. O'Farrell, T. J. Abrams, H. A. Yuen, T. J. Ngai, S. G. Louie, K. W. H. Yee, L. M. Wong, W. Hong, L. B. Lee, A. Town, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo Blood, May 1, 2003; 101(9): 3597 - 3605. [Abstract] [Full Text] [PDF] J. Sohal, V. T. Phan, P. V. Chan, E. M. Davis, B. Patel, L. M. Kelly, T. J. Abrams, A. M. O'Farrell, D. G. Gilliland, M. M. Le Beau, et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657 Blood, April 15, 2003; 101(8): 3188 - 3197. [Abstract] [Full Text] [PDF] K. Spiekermann, R. J. Dirschinger, R. Schwab, K. Bagrintseva, F. Faber, C. Buske, S. Schnittger, L. M. Kelly, D. G. Gilliland, and W. Hiddemann The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3 Blood, February 15, 2003; 101(4): 1494 - 1504. [Abstract] [Full Text] [PDF] F. Ravandi, M. Talpaz, and Z. Estrov Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550. [Abstract] [Full Text] [PDF] Z.-y. Wang Ham-Wasserman Lecture: Treatment of Acute Leukemia by Inducing Differentiation and Apoptosis Hematology, January 1, 2003; 2003(1): 1 - 13. [Abstract] [Full Text] [PDF] B. Lowenberg, J. D. Griffin, and M. S. Tallman Acute Myeloid Leukemia and Acute Promyelocytic Leukemia Hematology, January 1, 2003; 2003(1): 82 - 101. [Abstract] [Full Text] [PDF] M. L. Guzman, C. F. Swiderski, D. S. Howard, B. A. Grimes, R. M. Rossi, S. J. Szilvassy, and C. T. Jordan Preferential induction of apoptosis for primary human leukemic stem cells PNAS, December 10, 2002; 99(25): 16220 - 16225. [Abstract] [Full Text] [PDF] P. J. Houghton, P. C. Adamson, S. Blaney, H. A. Fine, R. Gorlick, M. Haber, L. Helman, S. Hirschfeld, M. G. Hollingshead, M. A. Israel, et al. Testing of New Agents in Childhood Cancer Preclinical Models: Meeting Summary Clin. Cancer Res., December 1, 2002; 8(12): 3646 - 3657. [Abstract] [Full Text] [PDF] R. Zheng, A. D. Friedman, and D. Small Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations Blood, December 1, 2002; 100(12): 4154 - 4161. [Abstract] [Full Text] [PDF] K. W. H. Yee, A. M. 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