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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3400-3408. Prepublished online as a Blood First Edition Paper on January 5, 2007; DOI 10.1182/blood-2006-06-029579. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2006-06-029579v1 109/8/3400    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shankar, D. B. Articles by Glaser, K. B. Search for Related Content PubMed PubMed Citation Articles by Shankar, D. B. Articles by Glaser, K. B. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia Deepa B. Shankar1, Junling Li2, Paul Tapang2, J. Owen McCall2, Lori J. Pease2, Yujia Dai2, Ru-Qi Wei2, Daniel H. Albert2, Jennifer J. Bouska2, Donald J. Osterling2, Jun Guo2, Patrick A. Marcotte2, Eric F. Johnson2, Niru Soni2, Kresna Hartandi2, Michael R. Michaelides2, Steven K. Davidsen2, Saul J. Priceman3, Jenny C. Chang1, Katrin Rhodes1, Neil Shah6, Theodore B. Moore1, Kathleen M. Sakamoto1,3,5, and Keith B. Glaser2 1 Division of Hematology/Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, and Mattel Children's Hospital Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California at Los Angeles (UCLA); 2 Cancer Research, R47J-AP9, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL; 3 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA; 4 Molecular Biology Institute, UCLA; 5 Division of Biology, California Institute of Technology, Pasadena, CA; 6 Division of Hematology-Oncology, Department of Medicine, University of California at San Francisco In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3–internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC50 approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC50 = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G0/G1 phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)–FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC50 approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC50 = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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