坎地沙坦对肝癌小鼠新生血管生成的抑制作用

Inhibitory effect of Candesartan on angiogenesis in hepatocellular carcinoma mice

目的:探讨坎地沙坦(血管紧张素Ⅱ1型受体拮抗剂)对肝癌小鼠新生血管生成的抑制作用。方法:将肝癌模型建模成功的100只BALB/C雄性小鼠随机分为5组,每组各20只。空白对照组(NEC组)给予0.9%生理盐水0.6 mL/d灌胃;低、中、高剂量坎地沙坦组(LCA组、MCA组、HCA组)分别给予50 mg/kg、100 mg/kg、200 mg/kg坎地沙坦灌胃;氟尿嘧啶组(5-FU组)给予5-FU 25 mg/kg腹腔注射。记录各组体重变化、瘤体体积、重量等指标;第9天随机抽取每组各10只小鼠脱颈处死,比较各组肿瘤组织血管内皮生长因子(VEGF)阳性评分、微血管密度(MVD)。记录各组剩余10只小鼠存活时间。结果:治疗4 d、6 d后,5-FU组体重均低于其余4组(P<0.05);治疗8 d后,各组体重比较:5-FU组<MCA组、HCA组<NEC组、LCA组(P<0.05)。治疗9 d后,各组瘤体体积、瘤体重量组间比较:NEC组>LCA组>MCA组>HCA组、5-FU组(P<0.05);抑瘤率组间比较:LCA组<MCA组、HCA组、5-FU组(P<0.05);VEGF阳性评分组间比较:NEC组、5-FU组>LCA、MCA组>HCA组(P<0.05);MVD组间比较:NEC组、5-FU组>LCA>MCA组>HCA组(P<0.05)。透射电镜显示,NEC组未见细胞凋亡;其余各组凋亡细胞数量由高到低排序为:HCA组、MCA组、LCA组和5-FU组。LCA、MCA、HCA、5-FU组建模至可见肿瘤时间均长于NEC组;各组平均存活时间比较:HCA组>MCA组、5-FU组>LCA组>NEC组(P<0.05)。结论:坎地沙坦可抑制肝癌小鼠移植瘤的生长和新生血管生成,延长小鼠生存时间,其抑制作用存在量效依赖性。

Objective:To investigate the inhibitory effect of angiotensin Ⅱ-1 receptor antagonist(AT1)Candesartan on angiogenesis in mice with hepatocellular carcinoma.Methods:100 BALB/C male mice with successful liver cancer model were divided into 5 groups,with 20 mice in each group.The blank control group(NEC group)were given 0.9%normal saline 0.6 mL/d by gavage,the low,medium and high dose groups(LCA group,MCA group and HCA group)were given 50 mg/kg,100 mg/kg and 200 mg/kg candesartan by gavage,respectively,Fluorouracil group(5-FU group)received 25 mg/kg intraperitoneal injection of 5-FU.The changes of body weight,tumor volume and weight were recorded in each group.On the 9th day,10 mice from each group were selected and sacrificed to compare vascular endothelial growth factor(VEGF)expression and microvascular density(MVD)in tumor tissues of each group.The survival time of another 10 mice in each group was recorded.Results:The body weight after 4 and 6 d of treatment in 5-FU groups was lower than that in NEC group,LCA group,MCA group and HCA group(P<0.05).After 8 days of treatment,the body weight of MCA group,HCA group and 5-FU group was lower than that of NEC group and LCA group,the body weight of 5-FU group was lower than that of MCA group and HCA group(P<0.05).Comparison of the tumor volume and weight after 9 d of treatment:NEC group>LCA group>MCA group>HCA group and 5-FU group(P<0.05).The antitumor rate of LCA group was lower than that of MCA group,HCA group and 5-FU group(P<0.05).Comparison of VEGF positive scores between groups:NEC group,5-FU group>LCA group,MCA group>HCA group(P<0.05).Comparison of MVD between groups:NEC group,5-FU group>LCA group>MCA group>HCA group(P<0.05).Transmission electron microscopy showed that no apoptosis was observed in NEC group.Transmission electron microscopy showed that there was no cell apoptosis in the NEC group,and the number of apoptotic cells in other groups was ranked from high to low was HCA group,MCA group,LCA group and 5-FU group.The time to tumor formation of LCA,MCA,HCA and 5-FU was longer than that of NEC group.Comparison of average survival time among different groups:HCA group>MCA group,5-FU group>LCA group>NEC group(P<0.05).Conclusion:AT1 can inhibit the growth and neovascularization of transplanted tumor,prolong the survival time of mice with hepatocellular carcinoma,and its inhibitory effect is dose-dependent.