COX-2选择性抑制剂塞来昔布对裸鼠荷人子宫内膜腺癌的抑制作用

Inhibitory Effect of Cyclooxygenase-2 Selective Inhibitor Celecoxib on Growth of Human Endometrium Adenocarcinoma Xenografts in Nude Mice

目的探讨环氧化酶-2(Cyclooxygenase-2,COX-2)选择性抑制剂塞来昔布对人子宫内膜腺癌的治疗作用及其机制。方法建立人子宫内膜腺癌HEC-1B细胞裸鼠荷瘤模型,待成瘤后随机分为对照组与实验组,对照组予生理盐水口服2周,实验组分别予塞来昔布4mg/d和2mg/d口服2周。从治疗开始每3天计算瘤体积一次,描绘肿瘤生长曲线,治疗结束后处死裸鼠剥除瘤组织,计算抑瘤率,采用RT-PCR法测定移植瘤组织COX-2mRNA的表达、免疫组化法测定COX-2蛋白的表达和微血管密度(MVD)。结果塞来昔布对裸鼠皮下移植瘤的生长具有明显的抑制作用,且随着药物浓度的增加,抑瘤作用逐渐增强(抑瘤率分别为32.4%和48.6%),RT-PCR结果显示移植瘤组织COX-2mRNA的表达逐渐减弱,免疫组化结果显示移植瘤组织COX-2蛋白的表达及微血管密度(MVD)逐渐减少,实验组与对照组之间及各实验组之间的差异均有统计学意义(P<0.05),COX-2蛋白的表达与MVD数量呈正相关(r系数为0.921,P<0.01)。结论COX-2选择性抑制剂塞来昔布能够抑制裸鼠荷人子宫内膜腺癌的生长,其机制可能与降低COX-2的表达、减少微血管的生成有关。

Objective To investigate the therapeutical effect of cyclooxygenase-2 selective inhibitor Celecoxib on human endometrium adenocarcinoma and its mechanism. Methods Human endometrium adenocarcinoma xenografts were established in nude mice. When the diameter of tumor was about 5 mm, the mice were divided into three groups randomely, which were treated with normal sodium, celecoxib of low dose （4 mg/d） and celecoxib of high dose （2 rag/d） respectively for two weeks. The size of the tumors were calculated every 3 days and tumor growth curve was depicted. At the end of the treatments, the mice were killed and the tumors were harvested. The tumor inhibition rate was calculated. The expression of COX-2 mRNA in tumor samples was detected by RT-PCR, and the expression of COX-2 protein and microvessel density were examined by immunohistochemistry. Results There was significantly inhibitory effect of celecoxib on xenografts in nude mice, and the tumor inhibition rates was upgraded （32. 4% and 48. 6% respectively） with the increase of celecoxib doses. RT-PCR results indicated that the expression of COX-2 mRNA was gradually decreased with the increase of celecoxib doses. Immunohistochemistry results revealed that the expression of COX-2 protein and microvessel density in tumor samples were gradually decreased with the increase of celecoxib doses. The differences between expreimental and control groups, as well as between two experimental groups were statistically significant（P〈0. 05）. The expression of COX-2 protein had positive correlation with microvessel density （r =0. 921, P〈0. 01 ）. Condusion Celecoxib can inhibit the growth of human endometrium adenocarcinoma xenografts in nude mice. The mechanism may be associated with down-regulation of COX-2 expression and the decrease of microvessel density in tumor tissue.