Defense Date

2009

Document Type

Thesis

Degree Name

Master of Science

Department

Biochemistry

First Advisor

Paul Dent

Abstract

Ovarian cancer is the most lethal gynecological malignancy among women. The current first-line treatments for ovarian cancer are cisplatin, carboplatin and paclitaxel. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Therefore, the resistance to cisplatin therapy has been a critical hurdle in the management of recurrent ovarian cancer. The mechanisms responsible for cisplatin resistance are not completely understood. In the search for new therapies to overcome/bypass cisplatin resistance, melanoma differentiation gene-7 (MDA-7) IL-24, which is a new cytokine, has anti-cancer efficacy by suppressing cell growth and inducing apoptosis in a broad range of tumor cells and does not induce any toxicity in normal cells, thus, making it a potentially effective therapeutic gene for ovarian cancer. The purpose of this study was to evaluate the potential therapeutic efficacy of MDA-7 to treat ovarian carcinoma. Since adenoviral-mediated MDA-7 gene therapy has been shown to be well tolerated and showed biological activity in clinical studies in the context of other carcinomas we assessed the anticancer effects of Ad.mda-7 and in combination with cis-platinum on ovarian cancer cells. Our results show that the purified recombinant MDA-7 protein, GST-MDA-7, and Ad.mda7 virus (5) induced growth arresst and apoptosis in ovarian cancer cells. However, the apoptosis induction was low and directly correlated with infectivity of Ad.mda-7 virus (5). The use of a modified Ad.mda-7 virus type5, Ad.mda-7 virus type(5/3), inhanced infectivity and significantly enhanced ovarian cancer cell killing in human ovarian cancer cell lines in vitro compared to unmodified Ad.mda-7 virus, Ad.mda-7 virus type5. Also Ad-mda7 synergizes with cis-platinum in vitro and enhances ovarian cancer cell death. Taken together, these findings demonstrate that MDA-7 is capable of promoting growth suppression and inducing cell death in ovarian cancer cells, at least OVCAR cells and support the pharmacological interest of the combination of MDA-7 and cis-platinum.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

July 2009

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