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.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0677
DOI: https://doi.org/10.17192/z2013.0677
URN: urn:nbn:de:hebis:04-z2013-06777
DDC: Medizin
Publikationsdatum:2013-11-25
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

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

Zusammenfassung:
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.

Summary:
Recent studies were able to identify the Hedgehog-pathway and its receptor Smoothened as a potential therapeutic target in pancreatic neuroendocrine neoplasms. The goal of this study was to evaluate the orally bioavailable Smo-antagonist LDE225 as a new therapeutic agent. Such an evaluation had not been performed for islet cell tumors. To investigate in vivo effectiveness, Rip1Tag2 transgenic mice were treated from week 5 till death with a dose of 80 mg/kg/d. Resected pancreata from treated and untreated mice were microscopically and immunohistochemically evaluated. Additionally, quantitative real-time-PCR for Hh target genes was performed on cDNA synthesized from isolated islet RNA. Microscopically, the treatment reduced tumor size by 95%. Median survival was significantly prolonged in treated mice (p<0,05). Quantitative real-time-PCR showed a clear downregulation of Hh target genes Gli1, Ptch1 and Hip1, confirming effective pharmacologic levels within the desired tissue site in vivo. The findings of this study suggest that the orally bioavailable Smo-antagonist LDE225 might provide new options in the therapy of pancreatic neuroendocrine neoplasms.

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