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" Development of the syrian hamster as a permissive immunocompetent animal model for the study of oncolytic adenoviruses: Evaluation of antitumor efficacy, vector safety, and the mechanism of tumor suppression "
Maria A. Thomas
W. S. M. Wold
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Latin Dissertation
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English
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| Record Number
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55158
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TL25112
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3324226
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| Main Entry
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Maria A. Thomas
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| Title & Author
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Development of the syrian hamster as a permissive immunocompetent animal model for the study of oncolytic adenoviruses: Evaluation of antitumor efficacy, vector safety, and the mechanism of tumor suppression\ Maria A. Thomas
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| College
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Saint Louis University
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| Date
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2006
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| Degree
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Ph.D.
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2006
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154
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| Abstract
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Oncolytic adenoviruses represent an innovative approach to cancer therapy. These vectors are typically evaluated in immunodeficient mice with human xenograft tumors. However, in addition to being immunodeficient, this model is limited because normal and cancerous mouse tissues are poorly permissive for human adenovirus replication. This prompted us to search for a model that more accurately reflects the use of oncolytic adenoviruses in cancer patients. To this end, we developed a novel Syrian hamster model that is both immunocompetent and replication-permissive. We found that human adenovirus replicates well in hamster cell lines, and we confirmed replication in the lungs. Oncolytic adenovirus injection demonstrated efficacy in three different hamster tumor models. Further, intratumoral oncolytic adenovirus injection resulted in suppression of primary and metastatic lesions, intratumoral replication and necrosis, vector entrance into the bloodstream, replication in the liver and lungs, and anti-adenovirus antibody induction. Our findings demonstrated that the hamster is a promising immunocompetent model that is permissive to human adenovirus replication in tumors as well as normal tissues, allowing evaluation of both efficacy and safety. Development of this model allowed exploration of interactions between the virus, tumor, normal organs, and the host immune system that previously could not be examined in either immune-deficient or non-permissive animal models utilized in the field. We were curious whether the immune response mounted upon adenovirus injection was instrumental or detrimental to antitumor efficacy. We hypothesized that the primary mechanism of tumor suppression by oncolytic adenoviruses is virus replication and lysis of infected tumor cells. Importantly, we discovered that the antitumor efficacy of oncolytic adenovirus therapy was significantly enhanced in immunosuppressed animals. We also found that immunosuppression allowed virus levels to remain elevated in the tumor for a prolonged period of time. Immunosuppression, thus, allowed sustained adenovirus oncolysis and substantially improved suppression of tumor growth. The Syrian hamster model has the potential to become a valuable tool for the evaluation of oncolytic adenoviruses. Findings such as the enhancement of efficacy in immunosuppressed hosts highlight the unique ability of this model to assess interactions between adenovirus and the host organism, including the tumor, immune system, and normal tissues.
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Health and environmental sciences; Biological sciences; Adenoviruses; Cancer; Hamster; Immunocompetent; Permissive; Syrian; Tumor suppression; Microbiology; Immunology; Medicine; 0992:Medicine; 0982:Immunology; 0410:Microbiology
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W. S. M. Wold
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Saint Louis University
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