New therapeutic options for the treatment of lung cancer by telomerase inhibition ; Neue Therapieoptionen zur Behandlung des Bronchialkarzinoms durch Telomeraseinhibition

The enzyme telomerase plays an important role in cell immortalization and hence cancer development. It can be detected in most kinds of tumors but is not expressed in the majority of healthy cells. Therefore, telomerase inhibition appears to be a promising approach for a specific cancer therapy with reduced side effects. The work presented here concentrated on the treatment of non-small cell lung cancer by telomerase inhibition and can be divided into three parts: 1. Characterization of the G-quadruplex stabilizing substance BRACO19 under biopharmaceutical and stability aspects. BRACO19 showed a poor permeability across biological barriers and was instable under physiological conditions. 2. Evaluation of cationic chitosan/PLGA nanoparticles as a carrier system for 2';-O-Methyl-RNA antisense oligonucleotides (2OMR), which was directed against the template region of the telomerase specific RNA hTR. The chitosan content in the particles considerably influenced the uptake improvement of 2OMR into cells. Despite a poor complex stability in physiological media a successful inhibition of telomerase activity in lung cancer cells could be achieved. 3. Targeted delivery of anti-telomerase siRNA to CD44-overexpressing lung cancer cells using hyaluronic acid modified DOTAP/DOPE liposomes. These liposomes efficiently bound siRNA, protected it from degradation by nucleases and increased its uptake into CD44-overexpressing lung cancer cells. The modification improved the colloidal stability of lipoplexes in cell culture medium and their cytotoxicity. ; Das Enzym Telomerase spielt eine wichtige Rolle bei der Immortalisierung von Zellen und damit auch bei der Entwicklung von Krebserkrankungen. Es wird in einer Vielzahl von Tumoren exprimiert, jedoch nicht in den meisten gesunden Zelltypen. Durch seine Hemmung erhofft man sich eine sehr spezifische und nebenwirkungsarme Krebstherapie. Die durchgeführten Arbeiten konzentrierten sich auf die Behandlung von nicht-kleinzelligen Lungenkrebs mittels Telomeraseinhibitoren und ...