SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2002-02-0531. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-02-0531v1 100/8/2941    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 Yee, K. W. H. Articles by Heinrich, M. C. Search for Related Content PubMed PubMed Citation Articles by Yee, K. W. H. Articles by Heinrich, M. C. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2002, Vol. 100, No. 8, pp. 2941-2949 NEOPLASIA SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase Kevin W. H. Yee, Anne Marie O'Farrell, Beverly D. Smolich, Julie M. Cherrington, Gerald McMahon, Cecily L. Wait, Laura S. McGreevey, Diana J. Griffith, and Michael C. Heinrich From the Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, and Portland Veterans Affairs Medical Center, Portland; and SUGEN, South San Francisco, CA Internal tandem duplication (ITD) in the juxtamembrane portion of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase (RTK), is the most common molecular defect associated with acute myeloid leukemia (AML). The high prevalence of this activating mutation makes it a potential target for molecularly based therapy. Indolinone tyrosine kinase inhibitors have known activity against KIT, another member of the type III RTK family. Given the conserved homology between members of this family, we postulated that the activity of some KIT inhibitors would extend to FLT3. We used various leukemic cell lines (BaF3, MV 4-11, RS 4;11) to test the activity of indolinone compounds against the FLT3 kinase activity of both wild-type (WT) and ITD isoforms. Both SU5416 and SU5614 were capable of inhibiting autophosphorylation of ITD and WT FLT3 (SU5416 concentration that inhibits 50% [IC50], 100 nM; and SU5614 IC50 10 nM). FLT3-dependent activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) was also inhibited by treatment in the same concentration ranges. FLT3 inhibition by SU5416 and SU5614 resulted in reduced proliferation (IC50, 250 nM and 100 nM, respectively) and induction of apoptosis of FLT3 ITD-positive leukemic cell lines. Treatment of these cells with an alternative growth factor (granulocyte-macrophage colony-stimulating factor [GM-CSF]) restored MAPK signaling and cellular proliferation, demonstrating specificity of the observed inhibitory effects. We conclude that SU5416 and SU5614 are potent inhibitors of FLT3. Our finding that inhibition of FLT3 induces apoptosis of leukemic cells supports the feasibility of targeting FLT3 as a novel treatment strategy for AML. © 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: P. P. Zarrinkar, R. N. Gunawardane, M. D. Cramer, M. F. Gardner, D. Brigham, B. Belli, M. W. Karaman, K. W. Pratz, G. Pallares, Q. Chao, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML) Blood, October 1, 2009; 114(14): 2984 - 2992. [Abstract] [Full Text] [PDF] S. Fukuda, P. Singh, A. Moh, M. Abe, E. M. Conway, H. S. Boswell, S. Yamaguchi, X.-Y. Fu, and L. M. Pelus Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3 Blood, July 9, 2009; 114(2): 394 - 403. [Abstract] [Full Text] [PDF] F. Breitenbuecher, B. Markova, S. Kasper, B. Carius, T. Stauder, F. D. Bohmer, K. Masson, L. Ronnstrand, C. Huber, T. Kindler, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML Blood, April 23, 2009; 113(17): 4063 - 4073. [Abstract] [Full Text] [PDF] K. S. Lee, S. R. Kim, S. J. Park, K. H. Min, K. Y. Lee, Y. H. Choe, S. Y. Park, O. H. Chai, X. Zhang, C. H. Song, et al. Mast Cells Can Mediate Vascular Permeability through Regulation of the PI3K-HIF-1{alpha}-VEGF Axis Am. J. Respir. Crit. Care Med., October 15, 2008; 178(8): 787 - 797. [Abstract] [Full Text] [PDF] S. Vempati, C. Reindl, S. K. Kaza, R. Kern, T. Malamoussi, M. Dugas, G. Mellert, S. Schnittger, W. Hiddemann, and K. Spiekermann Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential Blood, July 15, 2007; 110(2): 686 - 694. [Abstract] [Full Text] [PDF] Q. Yao, B. Weigel, and J. Kersey Synergism between Etoposide and 17-AAG in Leukemia Cells: Critical Roles for Hsp90, FLT3, Topoisomerase II, Chk1, and Rad51 Clin. Cancer Res., March 1, 2007; 13(5): 1591 - 1600. [Abstract] [Full Text] [PDF] O. Piloto, M. Wright, P. Brown, K.-T. Kim, M. Levis, and D. Small Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways Blood, February 15, 2007; 109(4): 1643 - 1652. [Abstract] [Full Text] [PDF] L. Mologni, E. Sala, S. Cazzaniga, R. Rostagno, T. Kuoni, M. Puttini, J. Bain, L. Cleris, S. Redaelli, B. Riva, et al. Inhibition of RET tyrosine kinase by SU5416. J. Mol. Endocrinol., October 1, 2006; 37(2): 199 - 212. [Abstract] [Full Text] [PDF] K. S. Lee, K. H. Min, S. R. Kim, S. J. Park, H. S. Park, G. Y. Jin, and Y. C. Lee Vascular Endothelial Growth Factor Modulates Matrix Metalloproteinase-9 Expression in Asthma Am. J. Respir. Crit. Care Med., July 15, 2006; 174(2): 161 - 170. [Abstract] [Full Text] [PDF] O. Piloto, B. Nguyen, D. Huso, K.-T. Kim, Y. Li, L. Witte, D. J. Hicklin, P. Brown, and D. Small IMC-EB10, an Anti-FLT3 Monoclonal Antibody, Prolongs Survival and Reduces Nonobese Diabetic/Severe Combined Immunodeficient Engraftment of Some Acute Lymphoblastic Leukemia Cell Lines and Primary Leukemic Samples. Cancer Res., May 1, 2006; 66(9): 4843 - 4851. [Abstract] [Full Text] [PDF] C. Reindl, K. Bagrintseva, S. Vempati, S. Schnittger, J. W. Ellwart, K. Wenig, K.-P. Hopfner, W. Hiddemann, and K. Spiekermann Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML Blood, May 1, 2006; 107(9): 3700 - 3707. [Abstract] [Full Text] [PDF] D. H. Albert, P. Tapang, T. J. Magoc, L. J. Pease, D. R. Reuter, R.-Q. Wei, J. Li, J. Guo, P. F. Bousquet, N. S. Ghoreishi-Haack, et al. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer Ther., April 1, 2006; 5(4): 995 - 1006. [Abstract] [Full Text] [PDF] M. M. Schittenhelm, S. Shiraga, A. Schroeder, A. S. Corbin, D. Griffith, F. Y. Lee, C. Bokemeyer, M. W.N. Deininger, B. J. Druker, and M. C. Heinrich Dasatinib (BMS-354825), a Dual SRC/ABL Kinase Inhibitor, Inhibits the Kinase Activity of Wild-Type, Juxtamembrane, and Activation Loop Mutant KIT Isoforms Associated with Human Malignancies Cancer Res., January 1, 2006; 66(1): 473 - 481. [Abstract] [Full Text] [PDF] R. W. Stam, M. L. den Boer, P. Schneider, P. Nollau, M. Horstmann, H. B. Beverloo, E. van der Voort, M. G. Valsecchi, P. de Lorenzo, S. E. Sallan, et al. Targeting FLT3 in primary MLL-gene-rearranged infant acute lymphoblastic leukemia Blood, October 1, 2005; 106(7): 2484 - 2490. [Abstract] [Full Text] [PDF] K. Kirito, N. Fox, N. Komatsu, and K. Kaushansky Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1{alpha} Blood, June 1, 2005; 105(11): 4258 - 4263. [Abstract] [Full Text] [PDF] D.-E. Schmidt-Arras, A. Bohmer, B. Markova, C. Choudhary, H. Serve, and F.-D. Bohmer Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases Mol. Cell. Biol., May 1, 2005; 25(9): 3690 - 3703. [Abstract] [Full Text] [PDF] S. Fukuda, H. E. Broxmeyer, and L. M. Pelus Flt3 ligand and the Flt3 receptor regulate hematopoietic cell migration by modulating the SDF-1{alpha}(CXCL12)/CXCR4 axis Blood, April 15, 2005; 105(8): 3117 - 3126. [Abstract] [Full Text] [PDF] D. K. Walters, E. P. Stoffregen, M. C. Heinrich, M. W. Deininger, and B. J. Druker RNAi-induced down-regulation of FLT3 expression in AML cell lines increases sensitivity to MLN518 Blood, April 1, 2005; 105(7): 2952 - 2954. [Abstract] [Full Text] [PDF] O. Piloto, M. Levis, D. Huso, Y. Li, H. Li, M.-N. Wang, R. Bassi, P. Balderes, D. L. Ludwig, L. Witte, et al. Inhibitory Anti-FLT3 Antibodies Are Capable of Mediating Antibody-Dependent Cell-Mediated Cytotoxicity and Reducing Engraftment of Acute Myelogenous Leukemia Blasts in Nonobese Diabetic/Severe Combined Immunodeficient Mice Cancer Res., February 15, 2005; 65(4): 1514 - 1522. [Abstract] [Full Text] [PDF] K.-T. Kim, K. Baird, J.-Y. Ahn, P. Meltzer, M. Lilly, M. Levis, and D. Small Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival Blood, February 15, 2005; 105(4): 1759 - 1767. [Abstract] [Full Text] [PDF] W. Fiedler, H. Serve, H. Dohner, M. Schwittay, O. G. Ottmann, A.-M. O'Farrell, C. L. Bello, R. Allred, W. C. Manning, J. M. Cherrington, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease Blood, February 1, 2005; 105(3): 986 - 993. [Abstract] [Full Text] [PDF] P. Brown, M. Levis, S. Shurtleff, D. Campana, J. Downing, and D. Small FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression Blood, January 15, 2005; 105(2): 812 - 820. [Abstract] [Full Text] [PDF] M. Wadleigh, D. J. DeAngelo, J. D. Griffin, and R. M. Stone After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies Blood, January 1, 2005; 105(1): 22 - 30. [Abstract] [Full Text] [PDF] K. W. H. Yee, M. Schittenhelm, A.-M. O'Farrell, A. R. Town, L. McGreevey, T. Bainbridge, J. M. Cherrington, and M. C. Heinrich Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells Blood, December 15, 2004; 104(13): 4202 - 4209. [Abstract] [Full Text] [PDF] I. J. Griswold, L. J. Shen, P. La Rosee, S. Demehri, M. C. Heinrich, R. M. Braziel, L. McGreevey, A. D. Haley, N. Giese, B. J. Druker, et al. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis Blood, November 1, 2004; 104(9): 2912 - 2918. [Abstract] [Full Text] [PDF] J. Cools, N. Mentens, P. Furet, D. Fabbro, J. J. Clark, J. D. Griffin, P. Marynen, and D. G. Gilliland Prediction of Resistance to Small Molecule FLT3 Inhibitors: Implications for Molecularly Targeted Therapy of Acute Leukemia Cancer Res., September 15, 2004; 64(18): 6385 - 6389. [Abstract] [Full Text] [PDF] P. Brown, S. Meshinchi, M. Levis, T. A. Alonzo, R. Gerbing, B. Lange, R. Arceci, and D. Small Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition Blood, September 15, 2004; 104(6): 1841 - 1849. [Abstract] [Full Text] [PDF] Y. Li, H. Li, M.-N. Wang, D. Lu, R. Bassi, Y. Wu, H. Zhang, P. Balderes, D. L. Ludwig, B. Pytowski, et al. Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody Blood, August 15, 2004; 104(4): 1137 - 1144. [Abstract] [Full Text] [PDF] M. Levis, R. Pham, B. D. Smith, and D. Small In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects Blood, August 15, 2004; 104(4): 1145 - 1150. [Abstract] [Full Text] [PDF] B. D. Smith, M. Levis, M. Beran, F. Giles, H. Kantarjian, K. Berg, K. M. Murphy, T. Dauses, J. Allebach, and D. Small Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia Blood, May 15, 2004; 103(10): 3669 - 3676. [Abstract] [Full Text] [PDF] S. A. Armstrong, M. E. Mabon, L. B. Silverman, A. Li, J. G. Gribben, E. A. Fox, S. E. Sallan, and S. J. Korsmeyer FLT3 mutations in childhood acute lymphoblastic leukemia Blood, May 1, 2004; 103(9): 3544 - 3546. [Abstract] [Full Text] [PDF] J. Cools, H. Quentmeier, B. J. P. Huntly, P. Marynen, J. D. Griffin, H. G. Drexler, and D. G. Gilliland The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia Blood, April 1, 2004; 103(7): 2802 - 2805. [Abstract] [Full Text] [PDF] K. Bagrintseva, R. Schwab, T. M. Kohl, S. Schnittger, S. Eichenlaub, J. W. Ellwart, W. Hiddemann, and K. Spiekermann Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells Blood, March 15, 2004; 103(6): 2266 - 2275. [Abstract] [Full Text] [PDF] A.-M. O'Farrell, J. M. Foran, W. Fiedler, H. Serve, R. L. Paquette, M. A. Cooper, H. A. Yuen, S. G. Louie, H. Kim, S. Nicholas, et al. An Innovative Phase I Clinical Study Demonstrates Inhibition of FLT3 Phosphorylation by SU11248 in Acute Myeloid Leukemia Patients Clin. Cancer Res., November 15, 2003; 9(15): 5465 - 5476. [Abstract] [Full Text] [PDF] W. Fiedler, R. Mesters, H. Tinnefeld, S. Loges, P. Staib, U. Duhrsen, M. Flasshove, O. G. Ottmann, W. Jung, F. Cavalli, et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia Blood, October 15, 2003; 102(8): 2763 - 2767. [Abstract] [Full Text] [PDF] Q. Yao, R. Nishiuchi, Q. Li, A. R. Kumar, W. A. Hudson, and J. H. Kersey FLT3 Expressing Leukemias Are Selectively Sensitive to Inhibitors of the Molecular Chaperone Heat Shock Protein 90 through Destabilization of Signal Transduction-Associated Kinases Clin. Cancer Res., October 1, 2003; 9(12): 4483 - 4493. [Abstract] [Full Text] [PDF] F. J. Giles, A. T. Stopeck, L. R. Silverman, J. E. Lancet, M. A. Cooper, A. L. Hannah, J. M. Cherrington, A.-M. O'Farrell, H. A. Yuen, S. G. Louie, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes Blood, August 1, 2003; 102(3): 795 - 801. [Abstract] [Full Text] [PDF] R. Grundler, C. Thiede, C. Miething, C. Steudel, C. Peschel, and J. Duyster Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor Blood, July 15, 2003; 102(2): 646 - 651. [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] 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]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020