艾瑞昔布联合奥沙利铂对裸鼠结肠癌移植瘤血管形成的影响

Effect of ericoxib combined with oxaliplatin on angiogenesis of colon cancer xenografts in nude mice

目的探讨艾瑞昔布联合奥沙利铂对人结肠癌HT-29细胞裸鼠移植瘤血管形成的影响。方法选取60只裸鼠构建人结肠癌HT-29细胞裸鼠皮下移植瘤模型,随机分为4组,每组15只。对照组给予生理盐水灌胃,艾瑞昔布组给予艾瑞昔布100 mg/(kg·d)灌胃,奥沙利铂组给予奥沙利铂30 mg/kg腹腔注射,联合用药组给予艾瑞昔布100 mg/(kg·d)灌胃和奥沙利铂30 mg/kg腹腔注射,均1次/d,每3 d 1次,连续干预14 d。实验结束时计算各组瘤体积及抑瘤率,ELISA法检测各组小鼠血清血管内皮生长因子(VEGF)、基质金属蛋白酶-2(MMP-2)水平,RT-PCR法检测瘤组织中VEGF和MMP-2的mRNA表达水平,免疫组化法检测瘤组织中VEGF、MMP-2蛋白表达情况及微血管密度(MVD)。结果艾瑞昔布组、奥沙利铂组、联合组用药组与对照组相比较瘤体均生长缓慢,且联合用药组抑瘤率明显高于艾瑞昔布组、奥沙利铂组(P均<0.05)。艾瑞昔布组、奥沙利铂组、联合用药组血清VEGF和MMP-2水平、瘤体组织中VEGF和MMP-2 mRNA和蛋白表达水平、瘤体组织中MVD均显著低于对照组(P均<0.05),且联合用药组均明显低于艾瑞昔布组、奥沙利铂组(P均<0.05)。结论艾瑞昔布联合奥沙利铂可协同抑制人结肠癌裸鼠移植瘤肿瘤生长及血管形成,作用机制可能与下调VEGF、MMP-2表达有关。

Objective It is to investigate the effects of ericoxib combined with oxaliplatin on angiogenesis of human colon cancer HT-29 cells in nude mice.Methods Firstly,60 nude mice were selected to construct subcutaneous xenograft models of human colon cancer HT-29 cells,then they were randomly divided into 4 groups,15 mice in each group.The control group was given normal saline by intragastric administration,the irixibu group was given irixibu 100 mg/(kg·d)by intragastric administration,the oxaliplatin group was given oxaliplatin 30 mg/kg by intraperitoneal injection,and the combined medication group was given irixibu 100 mg/(kg·d)by intragastrical administration and oxaliplatin 30 mg/kg by intraperitoneal injection,all once per day,once every 3 days,and continued for 14 days.At the end of the experiment,the tumor volume and tumor inhibition rate of each group were calculated.The levels of serum vascular endothelial growth factor(VEGF)and matrix metalloproteinase-2(MMP-2)in mice of each group were measured by ELISA.RT-PCR was used to detect the expression levels of VEGF and MMP-2 mRNA in tumor tissue,and immunohistochemistry was used to detect the expression of VEGF and MMP-2 protein in tumor tissue and microvessel density(MVD).Results Compared with the control group,the tumors in the irixibu group,oxaliplatin group,and combination group were grew slower than the control group,and the tumor inhibition rate of the combination group was significantly higher than that in the irixibu group and oxaliplatin group(P<0.05).The levels of serum VEGF and MMP-2,the expression levels of VEGF and MMP-2 mRNA and protein in tumor tissues,and the MVD in tumor tissues were significantly lower in the irixibu group,oxaliplatin group,and combination therapy group than those in the control group(P<0.05),and the combination medication group was significantly lower than the irixibu group and oxaliplatin group(P<0.05).Conclusion Celecoxib combined with oxaliplatin can synergistically inhibit tumor angiogenesis in human colon cancer xenografts and enhance the anti-tumor effect of oxaliplatin.The mechanism may be related to the down-regulation of VEGF and MMP-2 expression.