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Charakterisierung experimenteller c-ABL/c-Src duale Kinase Hemmstoffe in der Therapie des nicht-kleinzelligen Adenokarzinoms der Lunge

: Krüwel, T.
: Kalesse, M.; Borlak, J.

Hannover, 2009, 162 S.
Zugl.: Hannover, Univ., Master Thesis, 2009
Master Thesis
Fraunhofer ITEM ()
targeted therapy; NSCLC; c-Abl; c-Src; kinase inhibitor

Background: Lung cancer is a leading cause of cancer-related morbidity. Henceforth novel strategies in the treatment of cancer are in need to improve survival and patient outcome. In this regard, the tyrosine kinases c-ABL and c-Src are interesting targets as their deregulation in tumor growth, proliferation and metastasis has been observed. Objective: To characterize a series of experimental c-ABL/c-Src dual kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC), colorectal and hepatocellular carcinomas. Methods: The antiproliferative activity of the experimental drugs was determined with the MTS assay. Cell cycle progression and intracellular reactive oxygen species (ROS) were measured by flow cytometry, whereas the caspase-3/7-activity assay was determined by luminescence. Expression of the tyrosine kinases c-ABL and c-Src as well as some interacting partners was studied by Western blotting, while whole genome expression analysis allowed hypothesis generation. Results: Treatment with the dual kinase inhibitors reduced cell viability and caused a cell cycle arrest predominantly at G0/G1 and in the case of Si162 at G2/M. There was a remarkable cell line dependent response to the treatment effects with dual kinase inhibitors. Western blot analysis confirmed inhibition of c-Src and a decrease of the expression of epidermal growth factor receptor (EGFR). For Si162, microarray analyses evidenced regulation of cell cycle dependent genes. Conclusion: Several dual kinase inhibitors were characterized that displayed promising therapeutic efficiency. Especially Si162 appeared to be most effective against a variety of tumor cell lines.