Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks.
Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks.
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DOI：
10.1615/jenvironpatholtoxicoloncol.v21.i2.130
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
E. Moran
中科院分区：
文献类型：
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作者：
E. Moran
众所周知，大约70%的癌症病例是由于环境、饮食或生活方式因素造成的。因此，这些情况可以通过适当的修改来避免。此外，在流行病学观察到非甾体抗炎药（NSAID）在结肠癌预防中的有益作用后，积极的化学预防已成为一种主要的干预方法。这主要是由于环加氧酶（考克斯）酶的抑制。考克斯酶系统包括两种同工酶，考克斯-1和考克斯-2，其将花生四烯酸转化为胡萝卜素。考克斯-1在胃肠道中组成型表达并合成细胞保护性的胡萝卜素。考克斯-2可由癌基因ras和scr以及其它细胞因子诱导;它在人癌细胞中过表达，其中它刺激细胞分裂和血管生成并抑制细胞凋亡。NSAID恢复细胞凋亡并减少肿瘤有丝分裂和血管生成。已经发现大多数癌细胞表现出考克斯-2的过表达。流行病学研究表明，摄入NSAID后患结肠癌、乳腺癌、食道癌和胃癌的风险较低。使用低剂量的非甾体抗炎药与腺瘤性息肉和明显结肠癌风险的统计学显著降低相关。舒林酸对结肠异常隐窝病灶（被认为是腺瘤的前体）和结肠腺癌的消退作用特别令人关注，因为这种NSAID对考克斯没有抑制作用。这可能支持这样的观点，即NSAID的抗炎作用也可能是由于考克斯-2抑制以外的机制。在乳腺癌中，大型队列研究报告了40%至50%的癌症发生风险降低，原发肿瘤的尺寸较小，并且累及腋窝淋巴结的数量减少。在食管和胃中也有类似的发现，但在贲门腺癌中没有报道。选择性考克斯-2抑制剂的最新发展导致了比一般NSAID更好的临床耐受性，并且没有已知在抑制考克斯-1后发生的胃肠道副作用。这些新药物在家族性腺瘤性息肉病、结肠癌、乳腺癌和前列腺癌中已获得令人鼓舞的结果。
It is well known that about 70% of cancer cases are due to environmental, dietary, or lifestyle factors. Accordingly, these cases maybe avoided by appropriate modifications. In addition, active chemoprevention has become a major interventional approach following the epidemiological observation of a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer prevention. This is chiefly due to the inhibition of the cyclooxygenase (COX) enzymes. The COX enzymatic system includes two isoenzymes, COX-1 and COX-2, that convert arachidonic acid to prostaglandins. COX-1 is constitutively expressed and synthesizes cytoprotective prostaglandins in the gastrointestinal tract. COX-2 is inducible by the oncogenes ras and scr and other cytokines; it is overexpressed in human cancer cells in which it stimulates cellular division and angiogenesis and inhibits apoptosis. NSAIDs restore apoptosis and decrease tumor mitogenesis and angiogenesis. Most cancer cells have been found to exhibit overexpression of COX-2. Epidemiological studies showed a lower risk of developing cancer of the colon, breast, esophagus, and stomach following the ingestion of NSAIDs. The use of NSAIDs in low dose was associated with a statistically significant decrease in the risk of adenomatous polyps and of overt colon cancer. The regressive effects of sulindac on foci of aberrant crypts in the colon (considered to be precursors of adenoma), and on adenocarcinoma of the colon, are of particular interest because this NSAID does not have an inhibitory effect on COX. This may support the view that the antineoplastic effect of NSAIDs may also be due to a mechanism other than COX-2 inhibition. In breast cancer, large cohort studies reported a 40 to 50% reduced risk of developing cancer, a smaller size of the primary tumor, and a reduction in the number of involved axillary lymph nodes. Similar findings have been reported in the esophagus and stomach, but not in gastric cardia adenocarcinoma. The recent development of selective COX-2 inhibitors resulted in better clinical tolerance than that associated with NSAIDs in general, with the absence of gastrointestinal side effects known to occur after the inhibition of COX-1. Encouraging results have been obtained with these new agents in familial adenomatous polyposis, colon, breast, and prostate cancer.