Tuynman J B, Peppelenbosch M P, Richel D J
Department of Medical Oncology, Academic Medical Center, F4-223, Meibergdreef 9, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
Crit Rev Oncol Hematol. 2004 Nov;52(2):81-101. doi: 10.1016/j.critrevonc.2004.08.004.
The cyclooxygenase-2 (COX-2) enzyme has a fundamental role in the carcinogenesis of colorectal cancer. The anticarcinogenic mechanisms of NSAIDs are not completely understood and appear to be only partially dependent on inhibition tumoral COX-2. Moreover, the mechanisms of NSAIDs depend on the concentration. In experimental setting, at low levels NSAIDs downregulate the COX-2 gene in colorectal cancer cells, whereas at clinical relevant concentrations the production of prostaglandin E2 by enzymatic activity of COX-2 is diminished resulting in inhibition of the tumor angiogenesis. At higher levels NSAIDs and especially some selective COX-2 inhibitors are capable of COX-2 independent effects, such as apoptosis induction of tumor cells. In animal models, NSAIDs administration results in inhibition of angiogenesis and proliferation, induction apoptosis and prevention of metastasis. In clinical setting, NSAIDs and selective COX-2 inhibitors have the capacity to prevent the development of colorectal adenomas. We have summarized data regarding the role of COX-2 in CRC and discuss the multiple targets of NSAIDs in their anticarcinogenic action. However, the translation of these anticarcinogenic effects of NSAIDs to its clinical application as adjuvant therapy in CRC is hampered by a lack of randomized clinical trials with long-term follow-up.
环氧化酶-2（COX-2）在结直肠癌的致癌过程中起着重要作用。非甾体抗炎药（NSAIDs）的抗癌机制尚未完全明确，似乎仅部分依赖于对肿瘤COX-2的抑制。此外，NSAIDs的作用机制取决于其浓度。在实验环境中，低浓度时NSAIDs可下调结直肠癌细胞中的COX-2基因，而在临床相关浓度下，COX-2的酶活性导致前列腺素E2的产生减少，从而抑制肿瘤血管生成。高浓度时，NSAIDs尤其是一些选择性COX-2抑制剂能够产生不依赖于COX-2的作用，如诱导肿瘤细胞凋亡。在动物模型中，给予NSAIDs可抑制血管生成和增殖、诱导凋亡并预防转移。在临床环境中，NSAIDs和选择性COX-2抑制剂有能力预防结直肠腺瘤的发生。我们总结了关于COX-2在结直肠癌中作用的数据，并讨论了NSAIDs在其抗癌作用中的多个靶点。然而，由于缺乏长期随访的随机临床试验，NSAIDs这些抗癌作用在结直肠癌辅助治疗中的临床应用受到了阻碍。
