Reovirus oncolysis and determinants of susceptibility

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2007
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Abstract
Reovirus represents a promising novel anti-cancer therapeutic and is presently being investigated in clinical trials for the treatment of diverse human cancers. The following dissertation aims to investigate the efficacy of reovirus as a cancer therapeutic and determine the factors that contribute to cellular susceptibility to oncolysis. My investigations led to a complete re-defining of the initial basis of reovirus oncolysis in which oncogenic Ras transformation was suggested to exclusively dictate permissiveness to therapy by releasing a block in viral gene translation, present in resistant cells. In this thesis, I demonstrate the therapeutic potential of reovirus against models of human lymphoid and epithelial malignancies, as well as a model of carcinogen-induced colon carcinomas in immunocompetent animals. I also outline several cell lines that exhibit a high resistance to reovirus oncolysis, and study persistent reovirus infection as a tool to be used in deciphering the molecular mechanism behind acquired resistance to reovirus. I find that resistant cells can be efficiently infected with tumor-adapted reovirus variants bearing mutations in their outer capsid proteins. I then demonstrate that infection with reovirus stripped of its outer capsid proteins by proteases, as well as the direct addition of protease into the culture medium of cells, renders previously restrictive cells susceptible to reovirus oncolysis. In contrast with the original model of reovirus oncolysis, my findings led to the discovery that proteolytic reovirus disassembly is a key determinant of reovirus oncolysis. As increased proteolytic activity within cancer cells is frequent, I conclude that this aberration in malignancies primarily dictates the permissiveness of cancers to reovirus, thereby proposing novel avenues for the optimization of reovirus oncolytic therapy.
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Bibliography: p. 226-263
Some pages are in colour.
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Citation
Alain, T. (2007). Reovirus oncolysis and determinants of susceptibility (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/1674
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