Cathcart Mary-Clare, O'Byrne Kenneth J, Reynolds John V, O'Sullivan Jacintha, Pidgeon Graham P
Department of Surgery, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James's Hospital, Dublin 8, Ireland.
Biochim Biophys Acta. 2012 Jan;1825(1):49-63. doi: 10.1016/j.bbcan.2011.09.004. Epub 2011 Oct 1.
Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE(2), which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA(2) in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD(2) and its metabolite 15d-PGJ2, PGF(1α) and PGI(2). Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity. A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field.
通过环氧化酶（COX）途径的花生四烯酸代谢会导致生物活性类二十烷酸的生成。在胃肠道（GI）恶性肿瘤的发生和发展过程中，类二十烷酸的表达水平会发生变化。COX-2是负责胃肠道癌症发生/发展的主要COX同工型。从正常状态发展到癌变状态的过程中，COX-2的表达会增加。观察性研究的证据表明，长期使用非甾体抗炎药（NSAID）可降低癌症发生风险，而每日服用阿司匹林可显著降低胃肠道癌症的发病率和死亡风险。多项随机对照试验（APC试验、散发性腺瘤性息肉预防试验、APPROVe试验）也显示，选择性COX-2抑制剂对患者具有显著的保护作用。然而，高剂量长期使用选择性COX-2抑制剂会增加心血管疾病风险，NSAID也与风险增加有关。最近，人们对COX信号的下游效应器在癌症发生/发展中的作用进行了研究。与EP和PPAR受体都结合的前列腺素E2（PGE(2)）是参与胃肠道癌症致癌作用的主要前列腺素。虽然还需要进一步研究来揭示血栓素A2（TXA(2)）在胃肠道癌症中的作用，但也已对其进行了研究。研究的其他前列腺素包括前列腺素D2（PGD(2)）及其代谢产物15d-15-脱氧前列腺素J2（15d-PGJ2）、前列腺素F(1α)（PGF(1α)）和前列环素（PGI(2)）。在胃肠道癌症中靶向这些前列腺素有望避免与长期选择性COX-2抑制相关的心血管毒性，同时保持抗肿瘤反应性。在胃肠道癌症中已确定了从正常到癌前再到恶性状态的渐进序列。在本综述中，我们将讨论COX衍生的前列腺素在胃肠道癌症发生和发展中的作用。还将讨论针对这些下游前列腺素进行胃肠道癌症化学预防和/或治疗的问题。最后，我们将重点介绍这一热门研究领域的最新临床前技术以及未来的研究方向。
