| 18556063 |
Kasper S, Breitenbuecher F, Hoehn Y, Heidel F, Lipka DB, Markova B, Huber C, Kindler T, Fischer T: The kinase inhibitor LS104 induces apoptosis, enhances cytotoxic effects of chemotherapeutic drugs and is targeting the receptor tyrosine kinase FLT3 in acute myeloid leukemia. Leuk Res. 2008 Nov;32(11):1698-708. Epub 2008 Jun 16.
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. |
84(1,1,1,4) |