选择性环氧合酶-2抑制剂对胃癌细胞生长的影响

目的　观察选择性环氧合酶 - 2 ( COX- 2 )抑制剂 (美洛昔康、塞来昔布、罗非昔布 )对人胃癌细胞株SGC790 1生长的影响以及罗非昔布对人胃癌裸鼠移植瘤生长的抑制效应。方法　采用 3H-胸腺嘧啶核苷 ( 3H- Td R)掺入法了解细胞的增殖 ;用免疫组化检测细胞增殖核抗原 ( PCNA)及细胞 COX- 2的表达 ;用 TUNEL 染色法检测细胞凋亡。建立人胃癌裸鼠原位移植瘤模型 ,给予罗非昔布 8周 ,观察肿瘤大小、COX- 2及 PCNA表达情况。结果三种选择性 COX- 2抑制剂均较阿司匹林更有效抑制体外培养的胃癌细胞 3H- Td R掺入 ,3H-胸腺嘧啶掺入值与药物浓度呈负相关。美洛昔康、塞来昔布、罗非昔布对胃癌细胞 3H-胸腺嘧啶掺入的 IC50 分别为 1.18× 10 - 7mol/ L、1.68× 10 - 8mol/ L、4.3 9× 10 - 9mol/ L。经 1× 10 - 5m ol/ L 的上述三种药物作用 2 4h,SGC790 1细胞凋亡指数分别为 19.8%± 1.8%、2 4.6%± 1.2 % 3 1.2 %± 2 .2 %。 COX- 2抑制剂的选择性越高 ,凋亡指数也显著升高 ( P<0 .0 1)。罗非昔布对裸鼠胃癌原位移植瘤的抑瘤率为 93 .9% ;肿瘤组织的 COX- 2、PCNA表达均较对照组明显下降。结论　COX- 2抑制剂的选择性越高 ,对胃癌生长抑制作用越强。罗非昔布可成为胃癌综合治疗的重要药物之一

The Effects of Selective Cyclooxygenase-2 Inhibitors on the Growth of Gastric Adenocarcinoma

OBJECTIVE: This study was aimed to compare the effects of three kinds of selective cyclooxygenase-2 inhibitors (meloxicam, celecoxib, rofecoxib on the growth of gastric adenocarcinoma SGC7901 cell line, and to observe the effect of rofecoxib, on transplanted gastric cancer of nude mice in vivo. METHODS: The proliferation and apoptosis of SGC7901 cells were measured by 3H-thymidine incorporation into DNA and the TdT-mediated dUTP nick end-labeling assay (TUNEL) separately. The expression of PCNA and COX-2 of gastric adenocarcinoma cells were detected by immunocytochemistry. Human gastric adenocarcinoma SGC7901 cells were implanted orthotopically in the stomach of nude mice. Rofecoxib (30 mg.kg-1.d-1) was administrated i.g. for eight weeks. RESULTS: All the drugs potentially decreased 3H-thymidine incorporation into SGC7901 cells. The inhibition effects showed a dose-dependence manner. The median-response concentration was: 1.18 x 10(-7) mol/L (meloxicam), 1.68 x 10(-8) mol/L (celecoxib), 4.39 x 10(-9) mol/L (rofecoxib). After treatment with meloxicam, celecoxib, rofecoxib (1 x 10(-5) mol/L) for 24 hours, the apoptosis indices of SGC7901 cells were: 19.8% +/- 1.8%, 24.6% +/- 1.2% and 31.2% +/- 2.2%, respectively. The higher selective inhibition on COX-2, the higher apoptosis index (P < 0.01). Rofecoxib down-regulated the expression of COX-2 and PCNA of SGC7901 cell, both in vitro and in vivo. The inhibition rate for xenografts in situ in nude mice treated with rofecoxib was 93.9%. CONCLUSION: The higher selective inhibition on COX-2, the stronger inhibition on gastric adenocarcinoma cells. Rofecoxib may be one of the important medicines in the treatment of gastric adenocarcinoma.