Reddy B S, Kawamori T, Lubet R A, Steele V E, Kelloff G J, Rao C V
Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, New York 10595, USA.
Cancer Res. 1999 Jul 15;59(14):3387-91.
Epidemiological and model studies with laboratory animals have provided evidence that nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer. Sulindac, a nonsteroidal anti-inflammatory drug, has been shown to inhibit azoxymethane (AOM)-induced colon carcinogenesis in rats when administered continuously before, during, and after carcinogen treatment (initiation and postinitiation periods) or when given continuously beginning 14 weeks after carcinogen administration (promotion/ progression stage). The present study was designed to investigate the chemopreventive efficacy of sulindac sulfone (exisulind), the sulfone metabolite of sulindac, when administered during the promotion/progression stage of colon carcinogenesis in comparison to the effect during the initiation and postinitiation periods. We have also studied the modulating effect of exisulind on colonic tumor apoptosis. At 5 weeks of age, groups of male F344 rats were fed diets containing 0%, 0.06%, and 0.12% exisulind. At 7 weeks of age, groups of animals were injected s.c. with AOM (15 mg/kg body weight, once weekly for 2 weeks). Animals intended for the promotion/progression study and receiving 0% exisulind were switched to an experimental diet containing 0.12% exisulind at 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, 50 weeks after the second AOM injection. Colon tumors were evaluated histopathologically for tumor type. Administration of 0.06% and 0.12% exisulind during the initiation and postinitiation periods significantly inhibited the incidence and multiplicity of invasive and/or noninvasive adenocarcinomas of the colon. The inhibition of colon tumorigenesis by exisulind was associated with a significant retardation of body weight gain shortly after sulfone administration and increased apoptosis in the colon tumors. In contrast, administration of the higher dose (0.12%) of exisulind during the promotion/progression stage had only minimal effects on colon tumorigenesis and apoptosis in the colon tumors, suggesting that early administration, but not late administration, may be required for chemopreventive efficacy of this drug.
流行病学研究及针对实验动物的模型研究均已证实，非甾体抗炎药可降低患结肠癌的风险。舒林酸作为一种非甾体抗炎药，已被证明在致癌物处理前、处理期间及处理后（启动期和启动后期）持续给药，或在致癌物给药14周后开始持续给药（促进/进展期）时，均可抑制大鼠体内由氧化偶氮甲烷（AOM）诱导的结肠癌发生。本研究旨在探究舒林酸砜（依西美坦），即舒林酸的砜代谢产物，在结肠癌发生促进/进展期给药时的化学预防效果，并与启动期和启动后期的效果进行比较。我们还研究了依西美坦对结肠肿瘤细胞凋亡的调节作用。5周龄时，将雄性F344大鼠分组，分别喂食含0%、0.06%和0.12%依西美坦的饲料。7周龄时，对各组动物进行皮下注射AOM（15mg/kg体重，每周一次，共2周）。计划进行促进/进展期研究且接受0%依西美坦的动物，在第二次AOM处理后14周，改为喂食含0.12%依西美坦的实验饲料。所有大鼠均维持各自的饮食方案直至研究结束，即第二次AOM注射后50周。对结肠肿瘤进行组织病理学评估以确定肿瘤类型。在启动期和启动后期给予0.06%和0.12%的依西美坦，可显著抑制结肠浸润性和/或非浸润性腺癌的发生率和多发性。依西美坦对结肠肿瘤发生的抑制作用与给药后不久体重增加显著减缓以及结肠肿瘤细胞凋亡增加有关。相比之下，在促进/进展期给予较高剂量（0.12%）的依西美坦，对结肠肿瘤发生和结肠肿瘤细胞凋亡的影响极小，这表明该药物的化学预防效果可能需要早期给药，而非晚期给药。
