The role of cyclooxygenase-2 inhibition for the prevention and treatment of prostate carcinoma.
The role of cyclooxygenase-2 inhibition for the prevention and treatment of prostate carcinoma.
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DOI：
10.3816/cgc.2003.n.020
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发表时间：
2003-09-01
期刊：
影响因子：
--
通讯作者：
Nelson, Peter S
中科院分区：
文献类型：
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作者：
Lin, Daniel W;Nelson, Peter S
实验和流行病学研究表明，非类固醇抗炎药(NSAIDs)在预防人类癌症方面是有效的。非类固醇抗炎药抑制环氧合酶(COX)酶，该酶具有将花生四烯酸转化为前列腺素(PG)的功能。环氧合酶-2是一种关键的环氧合酶同工酶，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迅速被诱导。环氧合酶-2催化的反应可能通过两种不同的机制参与肿瘤的发生：(1)。DNA损伤和(2)。PG介导的效应。由COX-2介导的反应形成的活性氧物种可直接诱导DNA氧化或激发致癌物的生物活性。前列腺素E2是环氧合酶-2介导的花生四烯酸代谢的副产物，已被证明具有促进肿瘤发生和肿瘤进展的多种生物学作用。这些作用包括促进细胞增殖，促进血管生成，以及上调抗凋亡蛋白Bcl-2的表达。此外，PGE2降低了自然杀伤细胞的活性，改变了免疫监视。体外实验研究发现，COX-2抑制剂抑制细胞增殖，促进细胞凋亡，并调节细胞周期调控相关基因。来自动物研究的证据支持非类固醇抗炎药在前列腺癌(CAP)预防中的作用。基于人群的研究已经观察到，在使用非类固醇抗炎药的男性中，CAP的发生率降低了。由于CAP的发展缓慢，男性很少在第六或七十岁之前发病，因此任何推迟或延长出现临床明显CAP的时间的策略，如化学预防策略，都将极大地影响这种疾病的自然病史。将介绍COX-2抑制在前列腺癌发生和CAP预防中作用的最新进展和关键分析。
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.