Dokument

Zusammenfassung:
Das duktale Adenokarzinom des Pankreas (PDAC) ist eine der am schlechtesten therapierbaren Krebserkrankungen überhaupt und verfügt über eine äußerst ungünstigste Prognose. Dies liegt unter anderem an der sich rasch entwickelnden Chemoresistenz des PDAC gegen das Standard-Chemotherapeutikum Gemcitabin. In den vergangenen Jahren zeigte die Substanzklasse der Hedgehog (Hh)-Inhibitoren vielversprechende Ansätze in in vitro-Versuchen sowie im xenotransplantierten Mausmodell verschiedenster Tumorentitäten, und mehrere Wirkstoffe befinden sich seit kurzem auch in klinischer Erprobung. LDE225 ist ein niedermolekularer Smoothened (SMO)-Antagonist, der schon in einigen Veröffentlichungen zu pankreatischen Tumoren zur Anwendung kam. In der vorliegenden Arbeit untersuchten wir die Wirkung der SMO-Inhibierung mit LDE225 auf die Tumorzelllinien Capan-1 und Panc-1. Explizit wurde die Fragestellung behandelt, inwiefern Chemoresistenz einen Einfluss auf die Effektivität einer Therapie mit SMO-Inhibitoren hat. Es wurden hierfür kommerziell verfügbare, Gemcitabin-sensitiven wildtyp-Zelllinien (wt), sowie eigens gezüchtete Gemcitabin-resistente Zelllinien (GR) verwendet. Es konnte gezeigt werden, dass LDE225 in ausreichend hoher Dosis die Proliferation der verwendeten Zelllinien hemmt. Nach der Erlangung von Chemoresistenz zeigte sich eine veränderte Wirksamkeit von LDE225 im Vergleich zu wt-Zellen. SMO-Inhibition verursachte in GR-Zellen keinen sensitivierenden Effekt gegenüber Gemcitabin. Der Einsatz von LDE225 führte nicht zu vermehrter Apoptose, doch es konnte eine Erhöhung der G1-Phase des Zellzyklus beobachtet werden. Mit Hilfe von quantitativer Analyse der Genexpression konnten Modifizierungen des Hh-Signalwegs nach SMO-Antagonisierung beschrieben werden. Während sich zahlreiche Veröffentlichungen den Effekten von Hh-Inhibitoren auf das Tumorstroma oder Krebsstammzellen widmen, untersucht die vorliegende Arbeit detailliert die Behandlung von Tumorzellen mit einem niedermolekularen SMO-Antagonisten und stellt Wechselwirkungen zwischen erworbener Chemoresistenz und der Aktivität des Hh-Signalweges im PDAC dar. Ziel ist es, Einblick in ein komplexes und bisher wenig beachtetes Gebiet zu gewinnen.

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