COX-1--Target for Ovarian Cancer Prevention & Treatment

COX-1——预防卵巢癌的靶点

• 批准号: 6997741
• 负责人: Sudhansu K Dey
• 金额: $ 14.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-22 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997741
• 关键词: cancer prevention; carcinogenesis; chemoprevention; disease /disorder model; fatty acid biosynthesis; genetically modified animals; human tissue; laboratory mouse; molecular oncology; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; ovary neoplasms; oxidoreductase inhibitor; prostaglandin endoperoxide synthase; prostaglandins

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.

卵巢癌是最致命的妇科恶性肿瘤，死亡率高，因此成为化学预防的目标，也是一个即将进行深入研究的候选者。卵巢癌的根本原因仍然难以捉摸，晚期疾病患者的治疗选择仍然不足。虽然有几项研究表明，使用非甾体抗炎药（NSAID）与降低患卵巢癌的风险有关，但其他研究未能检测到任何显着的关联。环加氧酶（考克斯）考克斯-1和考克斯-2催化前列腺素（PG）的生物合成。主要针对结直肠癌的研究已经证实，NSAID在癌症预防和已建立肿瘤的治疗中是有效的。这些药物被认为主要通过抑制考克斯-2来抑制癌症生长。考克斯-2在一系列结肠外癌症中也被上调，并且选择性考克斯-2抑制剂显示出有效的抗肿瘤作用。这些发现导致了几项临床试验的启动，这些试验测试了考克斯-2选择性抑制剂在预防癌症或作为已建立肿瘤的联合治疗的一部分中的功效。卵巢癌中考克斯亚型的表达模式仍存在争议。通过多种方法，我们的初步结果提供了证据，证明人和小鼠上皮性卵巢肿瘤均显示考克斯-1，而不是考克斯-2的高表达。界定是否 考克斯衍生的PG在卵巢癌中发挥任何作用，为了确定使用考克斯抑制剂预防和/或治疗该疾病是否存在科学依据，需要进行深入研究。我们推测考克斯-1衍生的PG通过上调促血管生成事件在卵巢上皮癌的发生和发展中起主要作用。我们将通过使用有或没有细胞减灭治疗的人卵巢癌样本、人卵巢癌细胞系和卵巢癌小鼠模型来检验我们的假设。我们的具体目标是：（1）从PG生物合成以及在执行促肿瘤作用中形成的主要PG的潜在作用机制方面表征卵巢癌模型，和（2）分析考克斯抑制剂对小鼠模型中卵巢肿瘤的起始和进展的作用。我们提出的以人和小鼠为模型系统的体内和体外遗传和分子方法将为更好地理解卵巢癌的预防和治疗提供有价值的信息。