Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis.
Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis.
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发表时间：
2000-01
期刊：
影响因子：
11.2
通讯作者：
B. Reddy;Y. Hirose;R. Lubet;V. Steele;G. Kelloff;Susan Paulson;Karen Seibert;C. Rao
中科院分区：
文献类型：
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作者：
B. Reddy;Y. Hirose;R. Lubet;V. Steele;G. Kelloff;Susan Paulson;Karen Seibert;C. Rao
流行病学观察和实验室研究表明，非甾体抗炎药（NSAID）可降低结肠癌的风险，NSAID对结肠癌发生的抑制作用是通过称为环加氧酶（COX）的限速酶调节前列腺素的产生来介导的。由于传统的NSAID抑制考克斯-1和考克斯-2，这些药物通过抑制组成型考克斯-1而引起副作用，例如胃肠道溃疡和肾毒性。考克斯-2在结肠肿瘤中过表达，因此，考克斯-2的特异性抑制剂可以作为化学预防剂。我们以前的研究表明，塞来昔布，一种考克斯-2的抑制剂，当在起始和起始后阶段给药时，在保留考克斯-1的同时，抑制氧化偶氮甲烷（AOM）诱导的结肠肿瘤发生，即，在致癌物治疗之前、期间和之后连续给予塞来昔布。本研究检查了塞来昔布在启动和启动后阶段给药的剂量反应效应。此外，在结肠癌发生的促进/进展阶段，即，在致癌物处理后14周开始，在雄性F344大鼠中测定连续塞来昔布给药。我们还测量了给予这种抑制剂的动物血浆中塞来昔布的稳态水平。对5周龄雄性F344大鼠组喂食对照饲料或含500、1000或1500 ppm塞来昔布的实验饲料。在7周龄和8周龄时，将预定进行致癌物处理的大鼠皮下注射。AOM的剂量率为15 mg/kg体重/周。在第二次AOM给药后14周，将预定用于促进/进展研究并最初接受对照饲料的动物组转换为含1500 ppm塞来昔布的饲料。所有大鼠保持其各自的饮食方案，直至研究结束，即，52周，然后处死。对结肠肿瘤进行组织病理学评价。在结肠腺癌的起始和后起始阶段给予500、1000或1500 ppm塞来昔布，以剂量依赖性方式显著抑制结肠腺癌的发生率（P <0.01至P < 0.0001）和多样性（P < 0.01至P < 0.0001）。重要的是，在促进/进展阶段给予1500 ppm塞来昔布也显著抑制结肠腺癌的发生率和多样性（P < 0.01）。此外，在启动和启动后阶段以及整个促进/进展阶段给予大鼠塞来昔布强烈抑制结肠肿瘤体积（P < 0.0002至P < 0.001）。塞来昔布的稳态血药浓度随剂量增加而略有增加。因此，在该模型系统中，当在启动和启动后阶段给予该考克斯-2抑制剂时，塞来昔布的化学预防功效具有剂量依赖性。这项研究首次证明，塞来昔布在结肠癌发生的促进/进展阶段也非常有效，表明在结肠肿瘤发展的后期阶段实现了化学预防功效。这表明塞来昔布可能是一种有效的化学预防剂，用于家族性腺瘤性息肉病和散发性息肉患者结肠癌的二级预防。
Epidemiological observations and laboratory research have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer and that the inhibition of colon carcinogenesis by NSAIDs is mediated through the modulation of prostaglandin production by rate-limiting enzymes known as cyclooxygenases (COXs). Because traditional NSAIDs inhibit both COX-1 and COX-2, these drugs induce side effects, such as gastrointestinal ulceration and renal toxicity, through the inhibition of the constitutive COX-1. Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 could serve as chemopreventive agents. Our previous study has shown that celecoxib, an inhibitor of COX-2, while sparing COX-1, inhibited azoxymethane (AOM)-induced colon tumorigenesis when administered during both initiation and postinitiation stages, ie., celecoxib administered continuously before, during, and after carcinogen treatment. This study examined the dose-response effect of celecoxib when administered during the initiation and postinitiation stages. In addition, the chemopreventive effects of high-dose celecoxib administered during the promotion/progression stage of colon carcinogenesis, ie., continuous celecoxib administration beginning 14 weeks after the carcinogen treatment, was determined in male F344 rats. We also measured the steady-state levels of celecoxib in the plasma of animals given this inhibitor. Groups of 5-week-old male F344 rats were fed either a control diet or experimental diets containing 500, 1000, or 1500 ppm celecoxib. At 7 and 8 weeks of age, rats scheduled for carcinogen treatment were injected s.c. with AOM at a dose rate of 15 mg/kg body weight/week. Groups of animals destined for the promotion/ progression study and initially receiving the control diet were switched to a diet containing 1500 ppm celecoxib beginning 14 weeks after the second AOM treatment. All rats remained on their respective dietary regimens until the termination of the study, ie., 52 weeks, and were then sacrificed. Colon tumors were evaluated histopathologically. Administration of 500, 1000, or 1500 ppm celecoxib during the initiation and postinitiation stages significantly inhibited the incidence (P < 0.01 to P < 0.0001) as well as the multiplicity (P < 0.01 to P < 0.0001) of adenocarcinomas of the colon in a dose-dependent manner. Importantly, administration of 1500 ppm celecoxib during the promotion/progression stage also significantly suppressed the incidence and multiplicity of adenocarcinomas of the colon (P < 0.01). Also, administration of celecoxib to the rats during the initiation and postinitiation periods and throughout the promotion/progression stage strongly suppressed colon tumor volume (P < 0.0002 to P < 0.001). The steady-state plasma concentration of celecoxib increases somewhat with the dose. Thus, in this model system, the chemopreventive efficacy of celecoxib is dose-dependent when this COX-2 inhibitor is administered during the initiation and postinitiation periods. This study provides the first evidence that celecoxib is also very effective when it is given during the promotion/progression stage of colon carcinogenesis, indicating that the chemopreventive efficacy is achieved during the later stages of colon tumor development. This suggests that celecoxib may potentially be an effective chemopreventive agent for the secondary prevention of colon cancer in patients with familial adenomatous polyposis and sporadic polyps.