选择性COX-2抑制剂塞来昔布预防胃癌前病变发生及其机制的研究  

Prophylactic Effect of a Selective COX-2 Inhibitor Celecoxib on Carcinogen-induced Gastric Premalignant Lesions in Rats

作　　者：唐保东[1] 曾志荣[1] 胡品津[1] 

机构地区：[1]中山大学第一附属医院消化内科,广东广州510080

出　　处：《癌症》2006年第10期1205-1209,共5页Chinese Journal of Cancer

基　　金：广东省自然科学基金(No.10713)~~

摘　　要：背景与目的:前期的动物实验表明,选择性环氧合酶(cyclooxygenase-2,COX-2)抑制剂塞来昔布可显著降低化学致癌剂N-甲基-NV-硝基-亚硝基胍(N-methyl-N5-nitro-N-nitrosoguanidine,MNNG)诱导的大鼠胃肿瘤发生率,但其对胃癌发生的重要中间阶段——胃癌前病变作用的研究甚少。本研究旨在探讨塞来昔布对胃癌前病变发生率的影响及其可能的机制。方法:94只清洁级雄性Wistar大鼠随机分为A、B、C、D、E5组。A组不作特殊处理;B组仅灌喂塞来昔布10mg/kg,每日1次;C组饮用含MNNG100!g/ml的蒸馏水;D组和E组除饮用含MNNG100!g/ml的蒸馏水外,D组灌喂塞来昔布10mg/kg每日1次,E组灌喂消炎痛3mg/kg,每日1次。实验前6周,每周一次用10%饱和氯化钠溶液1ml灌胃。16周时A、B、C、D、E组分别处死大鼠6只、8只、10只、10只、10只,其余大鼠在实验终点24周时处死。比较各组大鼠胃癌前病变发生率的差异,荧光定量PCR及免疫组化法检测胃粘膜COX-1、COX-2mRNA及蛋白水平,ELISA法测定胃粘膜PGE2水平。结果:93只大鼠完成实验,16周和24周时C、D、E组萎缩性胃炎的发生率均无显著性差异(P>0.05)。16周时各组均未见有异型增生改变;24周时C、D、E组异型增生发生率分别为75%(9/12)、25%(3/12)和46%(5/11)。与C组相比,D组异型增生发生率明显下降(P=0.039),而E组下降不显著(P=0.214)。16周、24周时各组胃粘膜COX-1表达水平均无显著性差异,C组COX-2表达水平(3.29±1.50、3.41±0.94)明显高于其他4组(P<0.001),而C组PGE2水平与D、E组相比差异无显著性(P>0.05)。结论:塞来昔布能有效降低化学致癌剂MNNG诱导的大鼠胃粘膜异型增生的发生率,而对胃粘膜组织PGE2表达水平无影响,提示这种效应可能通过非COX-2依赖途径实现。BACKGROUND ＆ OBJECTIVE： Although we have previously showed that a selective cyclooxygenase-2（COX-2） inhibitor celecoxib prevents gastric cancer development in a rat model of gastric carcinogenesis, the role of celecoxib on gastric premalignant lesions remains unknown. This study was to explore whether celecoxib was effective for the prevention of premalignancy, and further to clarify its mechanism. METHODS： Ninety-four male Wistar rats were divided into 5 groups. Group A （n=12） was fed with water only; group B （n=16） with daily 10 mg/kg celecoxib; group C （n=22） with 100μg/ml N- methyI-N＇-nitro-N-nitrosoguanidine （MNNG）; group D （n=22） with 100 μg/ml MNNG and daily 10 mg/kg celecoxib; group E （n=22） with 100 μg/ml MNNG and daily 3 mg/kg indomethacin. The rats in groups B to E were given 10% sodium chloride in the initial 6 weeks, and the rats in groups C to E were given 100 μg/ml MNNG in drinking water to induce premalignant lesions in the stomach. Six rats in group A, 8 in group B, 10 in group C, 10 in group D, and 10 in group E were killed at week 16, and others were killed at week 24. The occurrence rates of gastric premalignant lesions in the groups were compared. The mRNA and protein levels of COX-1 and COX-2 in gastric mucosa were determined by real-time polymerase chain reaction （PCR） and immunohistochemistry; prostaglandin E2 （PGE2） level was measured by an ELISA-based assay. RESULTS： Ninety-three rats were studied. In week 16 and week 24, the occurrence rates of glandular atrophy in groups C, D, and E had no significant difference （P〉0.05）. In week 16, gastric mucosal dysplasia was not detected in groups C, D, and E; at week 24, the occurrence rates of dysplasia were 75% （9/12） on group C, 25% （3/12） in group D, and 46% （5/11） in group E. The occurrence rate of gastric mucosal dysplasia was significantly lower in group D than in group C （25% vs. 75%, P=0.039）; there was no significant difference between group E and group C （46% vs.

关 键 词：胃肿瘤/药理学 N-甲基-N'-硝基-亚硝基胍 Wishar大鼠 COX-2抑制剂 塞来昔布 

分 类 号：R735.2[医药卫生—肿瘤]