Tang Bao-Dong, Zeng Zhi-Rong, Hu Pin-Jin
Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, P. R. China.
Ai Zheng. 2006 Oct;25(10):1205-9.
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.
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 100 microg/ml N-methyl-No-nitro-N-nitrosoguanidine (MNNG); group D (n=22) with 100 microg/ml MNNG and daily 10 mg/kg celecoxib; group E (n=22) with 100 microg/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 microg/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.
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. 75%, P=0.214). At week 16 and week 24, there was no significant difference in COX-1 expression between treatment groups and control group. The mRNA and protein levels of COX-2 in group C (3.29+/-1.50 and 3.41+/-0.94) were significantly higher than those in other groups (P<0.001). There was no significant difference in PGE2 level between groups C, D, and E (P>0.05).
Celecoxib effectively inhibits the development of gastric mucosal dysplasia in rats induced by MNNG, but has no effect on the PGE2 level in the gastric mucosa, indicating that the anti-neoplastic activities of celecoxib may be independent of COX-2.
尽管我们之前已表明选择性环氧化酶 -2（COX -2）抑制剂塞来昔布可在大鼠胃癌发生模型中预防胃癌发展，但其对胃癌前病变的作用仍不清楚。本研究旨在探讨塞来昔布对癌前病变预防是否有效，并进一步阐明其机制。
94只雄性Wistar大鼠分为5组。A组（n = 12）仅喂水；B组（n = 16）每日给予10 mg/kg塞来昔布；C组（n = 22）给予100 μg/ml N -甲基 -N -亚硝基胍（MNNG）；D组（n = 22）给予100 μg/ml MNNG并每日给予10 mg/kg塞来昔布；E组（n = 22）给予100 μg/ml MNNG并每日给予3 mg/kg吲哚美辛。B至E组大鼠在最初6周给予10%氯化钠，C至E组大鼠在饮用水中给予100 μg/ml MNNG以诱导胃内癌前病变。A组6只、B组8只、C组10只、D组10只和E组10只大鼠在第16周处死，其余在第24周处死。比较各组胃癌前病变的发生率。采用实时聚合酶链反应（PCR）和免疫组化法测定胃黏膜中COX -1和COX -2的mRNA和蛋白水平；采用基于酶联免疫吸附测定（ELISA）的方法检测前列腺素E2（PGE2）水平。
共研究93只大鼠。在第16周和第24周，C、D、E组的腺体萎缩发生率无显著差异（P>0.05）。在第16周，C、D、E组未检测到胃黏膜发育异常；在第24周，C组发育异常发生率为75%（9/12），D组为25%（3/12），E组为46%（5/11）。D组胃黏膜发育异常发生率显著低于C组（25%对75%，P = 0.039）；E组与C组之间无显著差异（46%对75%，P = 0.214）。在第16周和第24周，治疗组与对照组之间COX -1表达无显著差异。C组COX -2的mRNA和蛋白水平（3.29±1.50和3.41±0.94）显著高于其他组（P<0.001）。C、D、E组之间PGE2水平无显著差异（P>0.05）。
塞来昔布可有效抑制MNNG诱导的大鼠胃黏膜发育异常，但对胃黏膜中PGE2水平无影响，表明塞来昔布的抗肿瘤活性可能独立于COX -2。
