目的:探讨5-氟尿嘧啶(5-FU)联合选择性环氧合酶-2(Cox-2)抑制剂-塞来昔布(celecoxib)对人结肠癌裸鼠皮下移植瘤生长的影响及作用机制。方法:60只裸鼠建立人结肠癌裸鼠皮下移植瘤模型,模型建立后随机分为4组,分别给予塞来昔布及5-FU进行药物干预,成模28d后观察各组裸鼠实验前后的体质量变化、各组裸鼠瘤体体积、瘤质量,计算抑瘤率。Tunel方法检测凋亡指数(AI),电镜观察细胞凋亡形态,免疫组化及蛋白质印迹法检测各组细胞色素C、Caspase-3、Caspase-9以及Cox-2的表达水平。结果:各药物干预组肿瘤生长明显受抑制,塞来昔布干预组、5-FU干预组以及联合干预组抑瘤率分别为16.93%、56.16%和77.06%,P<0.01。电镜下见对照组瘤细胞无明显凋亡形态改变,而各干预组瘤细胞呈现明显凋亡形态改变,联合干预组凋亡表现尤为典型。各干预组较对照组肿瘤细胞凋亡明显增加,干预组各组之间AI比较差异有统计学意义,P<0.01。免疫组化及蛋白质印迹法显示,干预组Caspase-3、Caspase-9以及细胞色素C的表达水平明显高于对照组,且干预组各组之间比较其表达水平差异也有统计学意义,P<0.05;蛋白质印迹法检测结果显示,塞来昔布组及联合干预组的Cox-2表达明显低于对照组及5-FU干预组,其中联合治疗组表达水平最低。结论:塞来昔布与5-FU联合应用时具有明显的协同抗肿瘤作用,其机制可能不仅与塞来昔布具有协同抗肿瘤作用相关,还可能涉及5-FU通过基因水平的调控来进一步促进塞来昔布对Cox-2表达的抑制,进而显著上调细胞色素C、Caspase-3及Caspase-9蛋白表达,最终激活细胞色素C依赖性凋亡信号通路促进肿瘤细胞凋亡。 Objective: To investigate the effects of 5-fluorouracil (5-FU) combined with selective cyclooxygenase-2 (Cox-2) inhibitor celecoxib on the growth of human colon carcinoma xenografts in nude mice and its mechanism of action . METHODS: Sixty nude mice were established subcutaneously transplanted human colon cancer model in nude mice. After the model was established, they were randomly divided into 4 groups, which were treated with celecoxib and 5-FU respectively. After 28 days, the nude mice Before and after the change of body weight, tumor volume and tumor mass in each group, the tumor inhibition rate was calculated. Tunel method was used to detect the apoptosis index (AI). The morphology of apoptotic cells was observed by electron microscope. The expressions of cytochrome C, Caspase-3, Caspase-9 and Cox-2 were detected by immunohistochemistry and Western blotting. Results: The tumor growth was significantly inhibited in each drug-treated group. The inhibitory rates of celecoxib, 5-FU intervention group and combined intervention group were 16.93%, 56.16% and 77.06%, respectively, P <0.01. Under the electron microscope, the tumor cells in the control group showed no significant morphological changes of apoptosis, while the tumor cells in each intervention group showed obvious apoptotic morphological changes. The apoptosis in the combined intervention group was particularly typical. The apoptosis of tumor cells in each intervention group was significantly increased compared with the control group, AI in the intervention group was significantly different (P <0.01). Immunohistochemistry and Western blotting showed that the expression levels of Caspase-3, Caspase-9 and cytochrome C in the intervention group were significantly higher than those in the control group, and there was also a significant difference in the expression levels among the intervention groups (P < 0.05; Western blotting results showed that the expression of Cox-2 in celecoxib group and combined intervention group was significantly lower than that in control group and 5-FU intervention group, in which the combined treatment group had the lowest expression level. CONCLUSION: Celecoxib has a synergistic antitumor effect when used in combination with 5-FU. The mechanism may be related not only to the synergistic antitumor effect of celecoxib, but also to the regulation of 5-FU by gene regulation Promote the inhibition of Cox-2 expression of celecoxib, and then significantly upregulate the expression of cytochrome C, Caspase-3 and Caspase-9 protein, finally activate the cytochrome C-dependent apoptotic signaling pathway and promote the apoptosis of tumor cells.