Abstract
Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disorder characterized by tissue involvement and organ dysfunction due to abnormal eosinophil proliferation. In a subset of patients, this is caused by the FIP1L1-PDGFR-alpha fusion tyrosine kinase. Cumulative evidence indicates that the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec) is active for the treatment of patients with HES, particularly those expressing the FIP1L1-PDGFR-alpha oncoprotein. The novel tyrosine kinase inhibitor AMN107 was initially developed as a potent Bcr-Abl inhibitor based on the molecular structure of imatinib. We tested the in vitro efficacy of imatinib and AMN107 in the EOL-1 cell line and in cells from a patient with HES harboring the FIP1L1-PDGFR-alpha fusion kinase. AMN107 was as potent as imatinib in inducing apoptosis and inhibiting proliferation of EOL-1 cells, with IC(50) values of 0.54 and 0.20 nM, respectively. In addition, both drugs inhibited the phosphorylation of PDGFR-alpha tyrosine kinase with equivalent efficacy. We conclude that AMN107 and imatinib are active and equipotent against cells expressing the FIP1L1-PDGFR-alpha fusion gene.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Benzamides
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Caspase 3 / metabolism
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Caspase Inhibitors
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cytochromes c / antagonists & inhibitors
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Cytochromes c / metabolism
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Leukemic / drug effects
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Gene Expression Regulation, Leukemic / genetics
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Humans
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Hypereosinophilic Syndrome / metabolism
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Imatinib Mesylate
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Oncogene Proteins, Fusion / drug effects*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Phosphorylation
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Piperazines / pharmacology
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyrimidines / pharmacology*
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Receptor, Platelet-Derived Growth Factor alpha / drug effects*
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Receptor, Platelet-Derived Growth Factor alpha / genetics
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Receptor, Platelet-Derived Growth Factor alpha / metabolism
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mRNA Cleavage and Polyadenylation Factors / drug effects*
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mRNA Cleavage and Polyadenylation Factors / genetics
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mRNA Cleavage and Polyadenylation Factors / metabolism
Substances
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Antineoplastic Agents
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Benzamides
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Caspase Inhibitors
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Oncogene Proteins, Fusion
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Piperazines
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Poly(ADP-ribose) Polymerase Inhibitors
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Pyrimidines
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mRNA Cleavage and Polyadenylation Factors
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Imatinib Mesylate
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Cytochromes c
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Poly(ADP-ribose) Polymerases
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FIP1L1-PDGFRA fusion protein, human
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Protein-Tyrosine Kinases
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Receptor, Platelet-Derived Growth Factor alpha
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Caspase 3
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nilotinib