Alberts D S, Hixson L, Ahnen D, Bogert C, Einspahr J, Paranka N, Brendel K, Gross P H, Pamukcu R, Burt R W
Department of Medicine, University of Arizona, Tucson 85724, USA.
J Cell Biochem Suppl. 1995;22:18-23. doi: 10.1002/jcb.240590804.
Nonsteroidal antiinflammatory drugs (NSAIDs) have considerable potential as chemopreventive agents for colorectal cancer. Recent case-control drug surveillance and large cohort studies found that patients with regular aspirin use had a reduced incidence of colorectal cancer and/or decreased death rate from this disease. Several different NSAIDs reduce formation of both colon adenomatous polyps (the precursor lesion of colon cancer) and cancers in experimental animals given known carcinogens. Perhaps most convincing are reports that the NSAID sulindac promotes regression and inhibits recurrence of adenomatous colon polyps in patients with adenomatous polyposis coli. The best characterized pharmacologic effect of the NSAIDs is their reduction of prostaglandin synthesis by inhibiting prostaglandin synthetase PGE2, which catalyzes the formation of prostaglandin precursors from arachidonic acid. Several lines of evidence are contrary to the concept that inhibition of prostaglandin synthesis is central to the NSAIDs' chemopreventive effects. Relatively high levels of prostaglandins have been reported to inhibit tumor cell growth both in vivo and in vitro, and to inhibit differentiation in some tumor cell lines. We evaluated comparative chemopreventive effects on colon tumor formation in an azoxymethane (AOM)-induced colon carcinogenesis rat model using the NSAIDs piroxicam, sulindac, and sulindac sulfone, a metabolite of sulindac which lacks the anti-prostaglandin synthetase activity typically associated with NSAID-induced gastrointestinal toxicities. The results demonstrate that sulindac sulfone, a compound lacking anti-prostaglandin synthetase activity, inhibits AOM-induced colon cancer in rats. Substantial dose-dependent reductions in both tumor burden and tumor multiplicity were observed in the sulindac sulfone-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
非甾体抗炎药（NSAIDs）作为结直肠癌的化学预防剂具有相当大的潜力。最近的病例对照药物监测和大型队列研究发现，经常使用阿司匹林的患者结直肠癌发病率降低和/或该疾病的死亡率下降。几种不同的NSAIDs可减少给予已知致癌物的实验动物中结肠腺瘤性息肉（结肠癌的前体病变）和癌症的形成。也许最有说服力的是，有报道称NSAID舒林酸可促进结肠腺瘤性息肉病患者的腺瘤性结肠息肉消退并抑制其复发。NSAIDs最具特征的药理作用是通过抑制前列腺素合成酶PGE2来减少前列腺素合成，PGE2催化花生四烯酸形成前列腺素前体。有几条证据与前列腺素合成抑制是NSAIDs化学预防作用核心的概念相反。据报道，相对高水平的前列腺素在体内和体外均能抑制肿瘤细胞生长，并在某些肿瘤细胞系中抑制分化。我们使用NSAIDs吡罗昔康、舒林酸和舒林酸砜（舒林酸的一种代谢产物，缺乏通常与NSAID诱导的胃肠道毒性相关的抗前列腺素合成酶活性），在氧化偶氮甲烷（AOM）诱导的结肠癌大鼠模型中评估了对结肠肿瘤形成的比较化学预防作用。结果表明，舒林酸砜这种缺乏抗前列腺素合成酶活性的化合物可抑制大鼠AOM诱导的结肠癌。在舒林酸砜处理的动物中观察到肿瘤负荷和肿瘤多发性均有显著的剂量依赖性降低。（摘要截短为250字）
