Dokument

Zusammenfassung:
Eine häufige Eigenschaft von Tumorzellen ist die Fehlfunktion von Signalwegen, die den Zellzyklus regulieren, wodurch eine erhöhte Proliferations- und Mutationsrate ermöglicht wird. Zellen mit einer gestörten Funktion des p53-abhängigen DNA-Schaden-Signalwegs in der G1-Phase besitzen einerseits diese Tumor-fördernden Eigenschaften und sind andererseits vollständig auf den DNA-Schaden-Signalweg der G2-Phase angewiesen, um schädlichen DNA-Schaden reparieren zu können. Ein neues Konzept einer kombinierten Chemotherapie besteht in der sequentiellen Gabe einer DNA-schädigenden Substanz und eines CHK1-Inhibitors, welcher den DNA-Schaden-Signalweg der G2-Phase hemmt. Zellen mit gestörter p53-Funktion können so weder in der G1- noch in der G2-Phase arretieren, um eine DNA-Reparatur zu ermöglichen, und versterben in großer Zahl nach Eintritt in die Mitose. Die hierbei eingeleiteten mitotischen und apoptotischen Signalwege sind bisher nicht im Detail bekannt und sollten in dieser Arbeit weiter untersucht werden. Ich konnte zeigen, dass in Zellen, die nach Behandlung mit Adriamycin (Topoisomerase-II-Hemmstoff) und UCN-01 (CHK1-Hemmstoff) mitotisch arretieren, neben der Einleitung einer mitochondrialen Apoptose auch antiapoptotische Signalwege aktiviert werden. So kommt es zu einer Abnahme der aktiven Form des proapoptotischen Proteins Bax und einer Hyperphosphorylierung des antiapoptotischen Proteins Bcl-2. Durch zusätzliche Gabe von Roscovitine (CDK1-Hemmstoff) kann der Zelltod deutlich verstärkt werden, was möglicherweise in einer direkten antiapoptotischen Funktion von CDK1 in der Mitose oder einer Entblockung apoptotischer Signale durch den mitotischen Austritt begründet ist. Eine ähnliche Therapieverstärkung zeigte sich nach einer Kombination mit dem Aurora-B-Inhibitor ZM447439. Diese Ergebnisse stützen den allgemeinen Ansatz, Tumorzellen mit DNA-Schaden in die Mitose zu treiben und einen hierdurch eingeleiteten Zelltod durch Interaktion mit mitotischen oder apoptotischen Proteinen zu verstärken. Ob eine kombinierte sequentielle Chemotherapie aus DNA-Schädigung, CHK1-Inhibierung und CDK1-Inhibierung eine Option zur Effizienzsteigerung und Resistenzumgehung einer antiproliferativen Therapie darstellen könnte, müssen weitere Untersuchungen zeigen. Niedermolekulare CHK1- und CDK1-Inhibitoren befinden sich als Einzelsubstanzen oder Kombinationstherapien in der klinischen Erprobung.

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