Antiangiogenesis therapy of human ovarian cancer

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DESCRIPTION: (Applicant's Description) Background: The progressive growth and spread of ovarian carcinoma is dependent in part on the formation and maintenance of adequate blood supply, i.e., angiogenesis. We found that the expression of genes that regulate distinct steps in the process of angiogenesis correlates with the pattern and progressive growth of human ovarian carcinoma cells implanted into the peritoneal cavity of athymic nude mice: tumorigenicity correlated with expression of basic fibroblast growth factor (bFGF), and the production of ascites was directly correlated with expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), whereas progressive growth (and death of mice) was directly correlated with expression of interleukin-8 (IL-8). Overall Guiding Hypotheses and Specific Aims: The current results suggest two interdependent hypotheses: (I) the expression of angiogenesis-regulating genes in primary human ovarian cancer predicts the pattern of the disease and its clinical outcome; and (II) targeting the IL-8 gene which may enhance ovarian cancer growth and angiogenesis could offer new approaches to the treatment of ovarian cancer. The specific aims include the following: (1) to determine whether the expression of angiogenesis-related genes in primary ovarian cancers predicts disease pattern and clinical outcome; (2) to determine whether the expression of IL-8 is essential for the progressive growth of human ovarian cancer cells; (3) to determine whether the organ microenvironment (hypoxia, acidosis) can regulate the expression of IL-8 in human ovarian cancer cells; and (4) to determine whether inhibition of IL-8 expression by interferon-beta (IFN-beta) can inhibit angiogenesis and progressive (intraperitoneal) growth of human ovarian cancer. Significance: The proposed research will shed new light on the process of angiogenesis (with emphasis on the role of IL-8) which is crucial for the progressive growth of human ovarian cancer. A better understanding of the role of IL-8 in the progression of human ovarian cancer and how IL-8 expression is regulated will allow the design of new therapeutic approaches to downregulate the expression of IL-8 and, hence, inhibit tumor cell growth and angiogenesis initially in orthotopic models and later in the clinic.