The altered expression of genes which regulate apoptotic pathways may play an important role in the etiology of both breast and ovarian carcinoma. Furthermore, genes such as bcl-2 and bcl-X/L which are frequently overexpressed in breast and ovarian carcinoma may render these tumors resistant to treatment with radiation or chemotherapy. Based on the hypothesis that expression of these genes contributes to tumor progression and resistance, we have developed a strategy to block this pathway through transient expression of bcl-x/s, a competitive inhibitor of both bcl-2 and bcl-X/L via an adenovirus vector. This vector selectively induces apoptosis in breast and ovarian cancer cells in vitro while havining significantly less effect on normal breast cells. We propose to expand upon these findings in order to target apoptosis pathways as a clinical strategy for therapy of breast and ovarian carcinoma. In order to accomplish these objectives, we will first elucidate the molecular mechanisms accounting for the specificity of bcl-X/S induced apoptosis in tumor cells as compared to normal cells. We will then determine the ability of this vector to sensitize these cells to chemotherapy and radiation therapy induced apoptosis. We will compare the efficacy of bcl-X/S to other competitive inhibitors of this pathway including harakiri and mbm-2 described in Projects 1 and 3. In order to increase the efficacy of bcl-X/S adenoviral gene therapy we will test an approach utilizing the adenoviral E1A and E1B genes to facilitate transient viral replication. Based on these in vitro studies, we will test the efficacy of utilizing bcl-X/S adenoviral gene therapy in syngeneic and nude mouse models of breast and ovarian carcinoma. Finally, based on both the in vitro and animal models, we propose to develop a Phase I clinical trial to test the feasibility of utilizing bcl-X/S adenovirus in vitro to purge contaminating breast cancer cells in stem cell preparations from patients undergoing transplantation for metastatic breast cancer. We also propose to utilize bcl-X/S adenovirus as a local therapy for the control of ascites in ovarian carcinoma. These studies will determine the feasibility of targeting apoptosis pathways as a novel therapeutic strategy for breast and ovarian carcinoma.
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