Publikationsserver der Universitätsbibliothek Marburg

Titel:Evaluation des oral verfügbaren Smoothened-Antagonisten LDE225 zur Therapie von Inselzelltumoren in der transgenen Rip1Tag2-Maus
Autor:Wiese, Dominik
Weitere Beteiligte: Fendrich, Volker (Prof. Dr. med.)
URN: urn:nbn:de:hebis:04-z2013-06777
DDC:610 Medizin
Titel (trans.):Evaluation of the orally bioavailable Smoothened-antagonist LDE225 as therapy for islet cell tumors in transgenic Rip1Tag2-mice


Rip1Tag2, Hedgehog <Gen>, Neuroendokriner Tumor, Hedgehog, neuroendocrine tumor, transgen, transgenic, Rip1Tag2, Pankreas, pancreas

Der Hedgehog-Signalweg und sein Rezeptor Smoothened konnten in vorausgegangenen Studien als potenzieller therapeutischer Angriffspunkt bei pankreatischen neuroendokrinen Neoplasien identifiziert werden. Ziel dieser Arbeit war die Evaluation des oral bioverfügbaren Smo-Antagonisten LDE225 als neue Therapieoption. Dies war an einem Modell für Inselzelltumoren bisher nicht erfolgt. Um die in vivo Wirksamkeit zu untersuchen fand das transgene Rip1Tag2-Mausmodell für Inselzelltumoren Verwendung. Die Tiere der Therapiegruppe wurden mit LDE225 in der Dosierung 80mg/kg/d von der fünften Lebenswoche an, bis zu ihrem Tod behandelt. Die von therapierten und nicht therapierten Mäusen gewonnenen Pankreata wurden immunhistochemisch und histologisch aufgearbeitet. Zudem wurde aus isolierter Inselzell-RNA synthetisierte cDNA mittels quantitativer real-time-PCR auf die Expression der Hh-Zielgene untersucht. Histologisch verringerte die Behandlung die Tumorfläche um 95% gegenüber unbehandelten Rip1Tag2-Mäusen. Zudem überlebten im Survival-Versuch die therapierten Mäuse im Median signifikant länger als die Kontrollgruppe (p<0,05). Die quantitative real-time-PCR zeigte eine deutliche Expressions-Minderung der Hh-Zielgene Gli1, Ptch1 und Hip1, was ein Vorliegen effektiver Dosen des Wirkstoffes im Zielgewebe in vivo bestätigte. Die Ergebnisse dieser Arbeit zeigen, dass der oral verfügbare Smo-Antagonist LDE225 tatsächlich einen neuen Therapieansatz bei pankreatischen neuroendokrinen Neoplasien darstellen könnte.

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