Lin Daniel W, Nelson Peter S
Department of Urology, University of Washington, Seattle, WA 98109, USA.
Clin Prostate Cancer. 2003 Sep;2(2):119-26. doi: 10.3816/cgc.2003.n.020.
Experimental and epidemiologic studies have demonstrated that nonsteroidal antiinflammatory drugs (NSAIDs) are effective in the prevention of human cancers. Nonsteroidal antiinflammatory drugs inhibit the cyclooxygenase (COX) enzyme that functions to convert arachidonic acid to prostaglandins (PGs). Cyclooxygenase-2, a key COX isoenzyme, is rapidly induced in response to inflammatory stimuli, growth factors, cytokines, and promoters of neoplastic growth. Cyclooxygenase-2-catalyzed reactions may be involved in carcinogenesis via 2 distinct mechanisms: (1). DNA damage and (2). PG-mediated effects. Reactions mediated by COX-2 form reactive oxygen species that can directly induce the oxidation of DNA or instigate the bioactivation of carcinogens. Prostaglandin E2, a byproduct of COX-2-mediated arachidonic acid metabolism, exhibits several biologic actions that have been shown to promote tumorigenesis and tumor progression. These actions include increased cell proliferation, promotion of angiogenesis, and the elevated expression of the antiapoptotic protein Bcl-2. In addition, PGE2 decreases natural killer cell activity and alters immune surveillance. In vitro experimental studies find that COX-2 inhibitors decrease cellular proliferation, increase apoptosis, and modulate genes involved in cell cycle regulation. Evidence from animal studies supports a role for NSAIDs in prostate cancer (CaP) prevention. Population-based studies have observed a reduced incidence of CaP among men using NSAIDs. Because CaP evolves slowly and rarely strikes men before the sixth or seventh decade of life, any strategy to delay or lengthen the time to development of clinically evident CaP, such as chemoprevention strategies, would greatly impact the natural history of this disease. Recent progress and critical analyses in the roles of COX-2 inhibition on prostate carcinogenesis and CaP prevention will be presented.
实验和流行病学研究表明，非甾体抗炎药（NSAIDs）在预防人类癌症方面有效。非甾体抗炎药抑制环氧化酶（COX），该酶可将花生四烯酸转化为前列腺素（PGs）。环氧化酶-2（COX-2）是一种关键的COX同工酶，在炎症刺激、生长因子、细胞因子和肿瘤生长促进剂的作用下会迅速被诱导产生。COX-2催化的反应可能通过两种不同机制参与致癌过程：（1）DNA损伤和（2）PG介导的效应。由COX-2介导的反应会形成活性氧物种，其可直接诱导DNA氧化或促使致癌物的生物活化。前列腺素E2（PGE2）是COX-2介导的花生四烯酸代谢的副产物，具有多种生物学作用，已被证明可促进肿瘤发生和肿瘤进展。这些作用包括细胞增殖增加、血管生成促进以及抗凋亡蛋白Bcl-2的表达升高。此外，PGE2会降低自然杀伤细胞活性并改变免疫监视。体外实验研究发现，COX-2抑制剂可降低细胞增殖率、增加细胞凋亡并调节参与细胞周期调控的基因。动物研究的证据支持NSAIDs在预防前列腺癌（CaP）中的作用。基于人群的研究观察到，使用NSAIDs的男性中CaP发病率降低。由于CaP发展缓慢，且很少在男性60或70岁之前发病，因此任何延迟或延长临床明显CaP发病时间的策略，如化学预防策略，都将对该疾病的自然病程产生重大影响。本文将介绍COX-2抑制在前列腺癌发生和CaP预防中的作用的最新进展和批判性分析。
