Onkogene Signalwege bei der Infektion mit Adenoviren

Konditional replizierende Viren werden derzeit hinsichtlich ihrer Einsetzbarkeit in der Krebstherapie untersucht, mit dem Ziel der spezifischen, Virus-vermittelten Onkolyse. Ein vielversprechender onkolytischer Ansatz beruht auf der Beobachtung, dass aktiviertes Ras, wie es in 30 % aller malignen Tu...

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Bibliographic Details
Main Author: Schümann, Michael
Contributors: Dobbelstein, Matthias (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2005
Online Access:PDF Full Text
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Conditionally replicating viruses are currently being investigated regarding applicability in cancer therapy with the aim to achieve specific, virus-mediated oncolysis. One promising oncolytic approach is based on the observation that activated Ras, which occurs in 30% of all malignant tumors, may interfere with the activity of PKR, a central kinase of the cell’s antiviral response. PKR-sensitive viruses should thereby be able to selectively replicate in Ras-transformed tumor cells, while sparing the surrounding tissue. Initial promising experiments using reovirus and vesicular stomatitis virus, which are naturally sensitive to PKR action, were followed by experiments with PKR-sensitive virus mutants, such as influenza virus dNS1 and herpes simplex virus R3616. Disadvantages of these approaches are lacking genetic accessibility on the one hand, and high pathogenicity of the parental viruses on the other. Adenoviruses, however, only cause mild respiratory disease and are widely used as well characterized tools in gene therapy. In this dissertation, we successfully transferred the principle of Ras-mediated oncolysis onto adenoviruses. PKR-sensitive adenoviruses (Ad dVA) were created through targeted mutation, and their selective replication could be confirmed in various Ras-transformed tumor cells. Mechanistic studies, however, raised doubts about a generalizable concept of Ras-dependent replication of oncolytic viruses. Once, mutated Ras was not able to directly interfere with PKR activity. In addition, we found adenoviruses to actively trigger Ras-dependent signaling pathways to ensure efficient translation. We thus suspect indirect effects of Ras-dependent transformation on PKR effector mechanisms to be responsible for increased permissiveness of Ras-mutated tumor cells towards PKR-sensitive adenoviruses. In accordance with this hypothesis, the susceptibility of Ad dVA-permissive cells to PKR-mediated apoptosis was markedly decreased. Our findings generally support the applicability of PKR-sensitive adenoviruses in virus-mediated oncolysis, but concomitantly emphasize the necessity to fully elucidate the underlying mechanisms.