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

卵巢癌是一种迫在眉睫的密集研究对象，也是化学预防的目标，因为它是最致命的妇科恶性肿瘤，并与高死亡率相关。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。虽然几项研究表明，使用非类固醇抗炎药(NSAIDs)与降低患卵巢癌的风险有关，但其他研究未能发现任何显著的联系。环氧合酶(COX)酶COX-1和COX-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，非甾体抗炎药在预防癌症和治疗已有肿瘤方面是有效的。这些药物被认为主要通过抑制COX-2来抑制癌症生长。COX-2在一系列结肠癌中也表达上调，选择性的COX-2抑制剂显示出强大的抗肿瘤作用。这些发现导致了几项临床试验的启动，以测试COX-2选择性抑制剂在预防癌症或作为已建立的肿瘤联合治疗的一部分的有效性。COX亚型在卵巢癌中的表达模式仍相互矛盾。使用多种方法，我们的初步结果提供了证据，人类和小鼠卵巢上皮性肿瘤都显示出COX-1的高表达，而不是COX-2的表达。要定义是否 环氧合酶衍生的前列腺素在卵巢癌中发挥任何作用，为了确定是否存在使用环氧合酶抑制剂预防和/或治疗该疾病的科学依据，有必要进行深入研究。我们假设COX-1衍生的前列腺素通过上调促血管生成事件在卵巢上皮癌的发生和发展中发挥重要作用。我们将通过使用有或没有细胞减少治疗的人卵巢癌样本、人卵巢癌细胞株和卵巢癌小鼠模型来验证我们的假设。我们的具体目标是：(1)研究卵巢癌模型中PG的生物合成，以及在执行原癌效应过程中形成的主要PG的潜在作用机制；(2)分析COX抑制剂对小鼠卵巢肿瘤发生和发展的影响。我们提出的以人和小鼠为模型系统的体内和体外遗传学和分子生物学方法将为更好地了解卵巢癌的预防和治疗提供有价值的信息。

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.