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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2004-10-22
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pubmed:abstractText |
Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/4-(6-methoxy-7-(3-piperidin-1-ylprop...,
http://linkedlifedata.com/resource/pubmed/chemical/FLT3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Flt3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-kit,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/fms-Like Tyrosine Kinase 3
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0006-4971
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pubmed:author |
pubmed-author:BrazielRita MRM,
pubmed-author:DeiningerMichael W NMW,
pubmed-author:DemehriShadmehrS,
pubmed-author:DrukerBrian JBJ,
pubmed-author:GieseNeillN,
pubmed-author:GriswoldIan JIJ,
pubmed-author:HaleyAndrea DAD,
pubmed-author:HeinrichMichael CMC,
pubmed-author:La RoséePaulP,
pubmed-author:McGreeveyLauraL,
pubmed-author:ShenLei JLJ
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
104
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2912-8
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15242881-Animals,
pubmed-meshheading:15242881-Bone Marrow Cells,
pubmed-meshheading:15242881-Bone Marrow Transplantation,
pubmed-meshheading:15242881-Cell Cycle,
pubmed-meshheading:15242881-Colony-Forming Units Assay,
pubmed-meshheading:15242881-Female,
pubmed-meshheading:15242881-Graft Survival,
pubmed-meshheading:15242881-Humans,
pubmed-meshheading:15242881-Male,
pubmed-meshheading:15242881-Mice,
pubmed-meshheading:15242881-Mice, Inbred BALB C,
pubmed-meshheading:15242881-Mutation,
pubmed-meshheading:15242881-Piperazines,
pubmed-meshheading:15242881-Protein Kinase Inhibitors,
pubmed-meshheading:15242881-Proto-Oncogene Proteins,
pubmed-meshheading:15242881-Proto-Oncogene Proteins c-kit,
pubmed-meshheading:15242881-Quinazolines,
pubmed-meshheading:15242881-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:15242881-Tandem Repeat Sequences,
pubmed-meshheading:15242881-Transplantation, Homologous,
pubmed-meshheading:15242881-fms-Like Tyrosine Kinase 3
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pubmed:year |
2004
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pubmed:articleTitle |
Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis.
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pubmed:affiliation |
Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute, Portland 97239, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
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