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COX-2 inhibition in cancer therapeutics: a field of controversy or a magic bullet?

机译:在癌症治疗中抑制COX-2:争议的领域还是神奇的子弹?

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摘要

Carcinogenesis is a multistep process of long-term accumulation of genetic and epigenetic aberrations at the molecular level. Understanding the mechanisms underlying carcinogenesis could further provide insights for rationally designed new therapeutic strategies for cancer prevention and treatment. Epidemiological and experimental evidence supports the preventative effect of non-steroidal anti-inflammatory drugs (NSAIDs) regarding cancer development. NSAIDs inhibit cyclooxygenase (COX) activity, thus blocking the endogenous prostaglandin production. COX-2 is a key isoenzyme in this biochemical cascade and is inducible by various oncogenic stimuli. A large volume of research data has shown that COX-2 is often upregulated in many malignant tumours, rendering it an attractive candidate target for cancer therapeutics. Various possible direct mechanisms for COX-2 implication in carcinogenesis have been suggested, whilst intense interest has recently been focused on COX-2-independent effects of NSAIDs. Several COX-2-selective inhibitors are currently under evaluation in preclinical and clinical studies, either as single agents or in combination with conventional chemotherapy, radiotherapy and other new molecularly-targeted compounds, with promising results. This article critically reviews already published data on COX-2-selective inhibitors that have been tested in cancer clinical trials, highlights ongoing research and considers the future perspectives of this novel class of agents.
机译:致癌作用是分子水平上遗传和表观遗传畸变长期积累的多步骤过程。了解潜在的致癌机制可以进一步为合理设计新的癌症预防和治疗策略提供见识。流行病学和实验证据支持非甾体抗炎药(NSAIDs)对癌症发展的预防作用。 NSAIDs抑制环氧合酶(COX)的活性,从而阻止内源性前列腺素的产生。 COX-2是该生化级联反应中的关键同工酶,可由多种致癌刺激物诱导。大量研究数据表明,COX-2在许多恶性肿瘤中通常被上调,使其成为有吸引力的癌症治疗靶标。已经提出了多种可能的直接机制涉及COX-2的致癌作用,而近来人们一直非常关注NSAID的COX-2依赖性效应。目前正在临床前和临床研究中评估几种COX-2选择性抑制剂,这些抑制剂既可以作为单一药物,也可以与常规化学疗法,放射疗法和其他新的分子靶向化合物联合使用,并取得了可喜的结果。本文严格审查了已经在癌症临床试验中测试过的有关COX-2选择性抑制剂的已发表数据,强调了正在进行的研究并考虑了这种新型药物的未来前景。

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