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ASSESSING AN M MUTANT VESICULAR STOMATITIS VIRUS FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME BY DETERMINING APOPTOTIC MECHANISMS AND ANTIVIRAL RESPONSE

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abstract
Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM), an aggressive brain tumor. Matrix (M) protein mutants of VSV have shown greater selectivity for killing GBM cells versus normal brain cells, compared to VSV with wild-type M protein. The goal of experiments presented here was to determine mechanisms of M protein mutant (M51R) VSV induced apoptosis and how innate antiviral responses affect infection of GBM tumor cells. When compared to controls, U-87 GBM tumor cells expressing a dominant negative form of Fas (dnFas) or over-expressing Bcl-XL had reduced caspase-3 activation following infection with M51R VSV indicating that both the death receptor and mitochondrial pathways are important for M51R VSV induced apoptosis. Direct activation of Fas in Bcl-XL over-expressing cells inhibited caspase activation indicating that U-87 cells behave as type II cells. Inhibition of apoptosis in vitro delayed, but did not prevent virus-induced cell death. Murine xenografts of U-87 cells over-expressing Bcl-XL regressed with a similar rate to control cells following M51R VSV infection. Immunohistochemical analysis demonstrated similar levels of viral antigen expression, but reduced activation of caspase-3 following virus treatment of Bcl-XL-over-expressing tumors compared to controls.
subject
brain tumor
cell death
IL-6
interferon
oncolytic virus
vesicular stomatitis virus
contributor
Cary, Zachary Dylan (author)
Lyles, Douglas S (committee chair)
Ornelles, David (committee member)
Caldas, Hannah (committee member)
Hollis, Thomas (committee member)
Wilkinson, John C (committee member)
date
2011-07-14T20:36:25Z (accessioned)
2013-07-14T08:30:10Z (available)
2011 (issued)
degree
Biochemistry and Molecular Biology (discipline)
embargo
2013-07-14 (terms)
identifier
http://hdl.handle.net/10339/33497 (uri)
language
en (iso)
publisher
Wake Forest University
title
ASSESSING AN M MUTANT VESICULAR STOMATITIS VIRUS FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME BY DETERMINING APOPTOTIC MECHANISMS AND ANTIVIRAL RESPONSE
type
Dissertation

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