坎地沙坦对小鼠肝癌移植瘤及新生血管生成的抑制作用

The inhibitory effect of candesartan on growth and angiogenesis of mice bearing hepatocellular carcinoma xenograft

目的 探讨血管紧张素Ⅱ1型受体拮抗剂坎地沙坦对小鼠肝癌移植瘤生长及血管生成的影响.方法 建立肝癌H22细胞小鼠移植瘤模型.将48只小鼠随机分为生理盐水组（0.2ml d1～d8）、低剂量坎地沙坦组（2mg/kg,0.2ml d1～ds）、高剂量坎地沙坦组（20mg/kg,0.2ml d1～d8）和氟尿嘧啶组（25 mg/kg,0.2ml d1～d6）,每组12只.第9天处死小鼠取瘤组织,测瘤重,计算抑瘤率；免疫组化法检测移植瘤组织内血管内皮生长因子（VEGF）和CD34表达,测定微血管密度（MVD）.另取40只小鼠以相同条件进行平行实验,每组10只,观察小鼠的生存时间.结果 高剂量坎地沙坦组及氟尿嘧啶组的抑瘤率分别为35.3％和50.6％,均高于低剂量坎地沙坦组的20.7％,差异有统计学意义（P＜0.05）；与生理盐水组相比,低剂量（5.083±1.240）与高剂量坎地沙坦组（4.083±1.165） VEGF分值均显著降低（P＜0.05）,且高剂量组降低更明显（P＜0.05）；与生理盐水组相比,低剂量（20.633±2.171）与高剂量（17.150±2.713）坎地沙坦组MVD均显著降低（P＜0.01）,且高剂量组降低更明显（P＜0.05）；高剂量坎地沙坦组及氟尿嘧啶组小鼠的生命延长率分别为39.5％和30.6％,均高于低剂量坎地沙坦组的20.4％ （P ＜0.05）.结论 坎地沙坦可抑制小鼠肝癌移植瘤的生长,其机制可能与抑制肿瘤新生血管生成有关.

Objective To investigate the influence of angiotensin Ⅱ type 1 receptor blocker candesartan on growth and angiogenesis of mice bearing human hepatocellular carcinoma xenograft.Methods Fourty-eight mice bearing H22 hepatocellular carcinoma xenograft were established and randomly divided into normal saline group,low-dose candesartan group（2mg/kg）,high-dose candesartan group （20mg/kg）and flurouracil group（25mg/kg）with 12 in each group.Nine days after administration,the mice were sacrificed,and the weight of transplanted tumors was measured to calculate the tumor inhibitory rate.The immunohistochemical technology was adopted to detect the expressions of vascular endothelial growth factor（VEGF） and CD34 to calculate microvessel density（MVD）.The same test was applied to 40 mice to observe the survival time and calculate the life extension rate.Results The tumor inhibition rates in high-dose candesartan group（35.3％） and fluorouracil group（50.6％） were higher than 20.7％ in low-dose candesartan group（P ＜0.05）.Compared with the normal saline group,significant reduction of VEGF expression was observed in low-dose （5.083 ± 1.240） and high-dose candesartan（4.083 ± 1.165） with significance（P ＜ 0.05）.VEGF score in high-dose candesartan was lower than that in low-dose candesartan（P ＜0.05）.Compared with the normal saline group,the MVD in low-dose（20.633 ±2.171） and high-dose candesartan groups （17.150 ± 2.713） were significantly reduced（P ＜ 0.01）.Compared with low-dose candesartan group,the MVD in high-dose candesartan group were significantly reduced（P ＜0.05）.The life extension rates in low-dose candesartan group（20.4％） was lower than 39.5％ in high-dose candesartan group and 30.6％ in fluorouracil group （P ＜ 0.05）.Conclusion Candesartan is effective in inhibiting the growth of hepatocellular carcinoma xenograft,and the possible mechanism may be related to the inhibition of angiogenesis.