Ovarian cancer represents an impending candidate for intense research and a target for chemoprevention, because it is the most lethal gynecological malignancy and associated with a high mortality rate. The underlying causes of ovarian cancers remain elusive and treatment options for patients with advanced disease are still inadequate. While several studies suggest that the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk of developing ovarian cancer, other studies failed to detect any significant association. The cyclooxygenase (COX) enzymes, COX-1 and COX-2, catalyze prostaglandin (PG) biosynthesis. Research primarily on colorectal cancer has established that NSAIDs are effective in cancer prevention, and treatment of established tumors. These drugs are believed to inhibit cancer growth primarily by inhibiting COX-2. COX-2 is also upregulated in a range of extra-colonic cancers and selective COX-2 inhibitors show potent anti-neoplastic effects. These findings have led to the initiation of several clinical trials testing the efficacy of COX-2 selective inhibitors in the prevention of cancer or as part of a combination therapy for established tumors. The expression pattern of COX isoforms in ovarian cancer remains conflicting. Using multiple approaches, our preliminary results provide evidence that both human and mouse epithelial ovarian tumors show heightened expression of COX-1, not COX-2. To define whether the COX-derived PGs play any role in ovarian cancer and to determine whether a scientific rationale exists for the use of COX inhibitors in the prevention and/or treatment of the disease, in-depth studies are warranted. We hypothesize that COX-1 derived PGs play a major role in the genesis and progression of ovarian epithelial cancer by upregulating proangiogenic events. We will test our hypothesis by using human ovarian cancer samples with or without cytoreductive treatment, human ovarian cancer cell lines and mouse models of ovarian cancers.
Our specific aims are to: (1) Characterize models of ovarian cancer with respect to PG biosynthesis as well as the potential mechanisms of actions of the dominant PGs formed in executing proneoplastic effects and (2) Analyze the effects of COX inhibitors on the initiation and progression of ovarian tumors in mouse models. Our proposed genetic and molecular approaches in vivo and in vitro using human and mice as model systems will provide valuable information for better understanding of prevention and treatment of ovarian cancers.
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