Date of Award

9-1999

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Jack Gauldie

Abstract

In our studies, we have used adenoviruses containing the genes for Angiostatin (Ad-Angiostatin) and IL-12 (Ad-IL12) for tumor therapy. The biological activity of the Ad-Angiostatin has been characterized using an artificial matrix which promotes the growth of blood vessels (Matrigel). We observed suppression of vessel growth in the Matrigel following treatment with Ad-Angiostatin demonstrating the inibitory activity of this virus. Treatment of growing tumor in mice with either Ad-Angiostatin or Ad-IL12 resulted in modest delays in tumor growth compared to tumors treated with viruses which did not contain any genes. Ad-IL-12 treatment also causes tumors to regress in a small fraction of the treated animals (13%). However, when used in combination, treatment with Ad-Angiostatin and Ad-IL12 resulted in tumor regression in 54% of the cases, a strong anti-tumor response by killer white blood cells, and the cured animals were resistant to further outgrowth of tumor. These results are the first to demonstrate the usefulness of combining angiogenesis inhibitors with cytokines using gene therapy. The rationale for this therapy is to limit the tumor size by attacking the vasculature with angiostatin, allowing the Interleukin-12 to activate killer white blood cells to respond against foreign products present in the tumor tissue. In this manner, the potential for the white blood cells to reject the tumor is increased as there is less tumor mass present. (Abstract shortened by UMI.)

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