Abstract
Activating mutations of FLT3 are found in approximately one-third of acute myeloid leukemia (AML)-cases and are considered to represent an attractive therapeutic target. In this study, we report that the hydroxystyryl-acrylonitrile compound LS104 inhibits proliferation and induces potent cytotoxic effects in FLT3 expressing leukemic cells in vitro. Immunoblot and phosphoprotein-FACS analysis demonstrated inhibiton of phosphorylation of FLT3-ITD and of its downstream targets. In pharmacokinetic studies, a rapid and dose dependent cellular uptake of LS104 lasting up to 11h could be demonstrated. Combination of LS104 with chemotherapeutic agents markedly enhanced cytotoxic effects. Recently, a phase I clinical trial investigating LS104 in refractory/relapsed hematologic malignancies has been initiated.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylonitrile / analogs & derivatives*
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Acrylonitrile / pharmacology
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Adult
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Aged
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Aged, 80 and over
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects*
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Blotting, Western
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Bone Marrow / drug effects
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Bone Marrow / metabolism
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects*
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Colony-Forming Units Assay
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Cytarabine / administration & dosage
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Daunorubicin / administration & dosage
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Drug Therapy, Combination
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Female
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Fluorescent Antibody Technique
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Male
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Mice
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Middle Aged
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Point Mutation
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Signal Transduction / drug effects
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Styrenes / pharmacology*
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Tissue Distribution
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Tumor Cells, Cultured
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
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fms-Like Tyrosine Kinase 3 / genetics
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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2-(benzylaminocarbonyl)-3-(3,4-dihydroxystyryl)acrylonitrile
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Styrenes
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Cytarabine
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FLT3 protein, human
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Flt3 protein, mouse
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fms-Like Tyrosine Kinase 3
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Acrylonitrile
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Daunorubicin