6533b856fe1ef96bd12b3203
RESEARCH PRODUCT
The kinase inhibitor LS104 induces apoptosis, enhances cytotoxic effects of chemotherapeutic drugs and is targeting the receptor tyrosine kinase FLT3 in acute myeloid leukemia.
Thomas KindlerDaniel B. LipkaFlorian H HeidelStefan KasperBoyka MarkovaChristoph HuberThomas FischerFrank BreitenbuecherYvette Hoehnsubject
AdultMaleCancer ResearchDaunorubicinmedicine.drug_classBlotting WesternFluorescent Antibody TechniqueApoptosisPharmacologyReceptor tyrosine kinaseTyrosine-kinase inhibitorStyrenesColony-Forming Units AssayMiceBone Marrowhemic and lymphatic diseasesAntineoplastic Combined Chemotherapy ProtocolsmedicineTumor Cells CulturedCD135AnimalsHumansPoint MutationTissue DistributionAgedCell ProliferationAged 80 and overbiologyAcrylonitrileDaunorubicinCytarabineMyeloid leukemiaCell DifferentiationHematologyMiddle Agedmedicine.diseaseLeukemiaLeukemia Myeloid AcuteOncologyfms-Like Tyrosine Kinase 3Fms-Like Tyrosine Kinase 3Cytarabinebiology.proteinCancer researchDrug Therapy CombinationFemalemedicine.drugSignal Transductiondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2008-11-01 | Leukemia research |