血管紧张素Ⅱ1型受体拮抗剂对裸鼠胰腺癌的抑制作用

Inhibitory effect of angiotensinⅡtype 1 receptor antagonist on pancreatic cancer of nude mice

目的:探讨选择性血管紧张素Ⅱ1型受体拮抗剂ZD7155对裸鼠胰腺癌的抑制作用及其作用机制。方法:60只裸鼠接种胰腺癌PaTu8988s细胞建立胰腺癌移植瘤模型,成瘤后随机分成对照组、低剂量(10 mg·kg^(-1)·d^(-1))ZD7155治疗组和高剂量(20 mg·kg^(-1)·d^(-1))ZD7155治疗组,每组20只。治疗10 d后每组各处死10只裸鼠.测量肿瘤体积.称取瘤体质量.免疫组化检测移植瘤新生血管的CD31表达,透射电镜观察细胞凋亡;其余裸鼠共治疗30 d.记录生存期并观察ZD7155的毒副作用等共49 d。结果:(1)对照组和低、高剂量治疗组的实体瘤平均体积分别为(35.8±6.7)、(21.5±6.1)、(10.7±4.1) cm^3(P<0.01)。(2)低剂量组以及高剂量组在治疗后10 d的平均抑瘤率分别为22.7%和44.6%(P<0.01).与对照组相比均具有统计学意义(P<0.01)。(3)对照组和低、高剂量组平均微血管数目分别为16.7±0.9、11.5±0.5、6.05±0.7(P<0.01)。(4)对照组细胞未见凋亡改变,两治疗组均可见大量典型的处于不同阶段的凋亡细胞。(5)治疗组裸鼠生存期较对照组显著延长(P<0.01),而且高剂量组裸鼠生存期较低剂量组亦显著延长(P>0.01)。(6)未见明显毒副作用。结论:选择性血管紧张素Ⅱ1型受体拮抗剂在体内能抑制胰腺癌细胞生长、抑制肿瘤血管生成、促进肿瘤细胞凋亡,可望成为治疗胰腺癌的安全有效药物。

Objective：To investigate the inhibitory effect of selective angiotensin Ⅱ type 1 receptor antagonist ZD7155 on pancreatic cancer xenografts of nude mice. Methods： Sixty nude mice were given subcutaneous injections of PaTu8988s cells to establish the pancreatic cancer xenograft models; then the animal models were evenly randomized into 3 groups： low-dose （10mg·kg^-1·d^-1）ZD7155, high-dose（20mg·kg^-1·d^-1）ZD7155 and normal saline groups. Ten mice in each group were sacrificed 10 d after treatment and the tumor sizes and body weights were measured. The microvessel density （MVD） was assessed by immunostaining of endothelial cells for CD31 and the cell apoptoses were observed by transmission electron microscope. Another thirty mice were treated for 30 days; the survival period of mice and toxicity of ZD7155 were observed till the 49th day of treatment. Results： Ten days after treatment, the mean tumor volumes in the control, low-dose and high-dose groups were （35.8±6.7） cm^3 , （21.5±6.1） cm^3 and （10.7±4.1） cm^3 , respectively（P〈0.01） ; the average tumor inhibitory rates in low-dose and high-dose groups were 22.7 % and 44.6 %, respectively, both significantly higher than that of the control group（P〈0. 01）. The mean numbers of capillary vessels in the control, low-dose and high-dose ZD7155 were 16.7±0.9, 11.5±0.5 and 6.05±0.7, respectively（P〈0.01）. Transmission electron microscope showed a lot of typical apoptotic cells at different stages in the 2 ZD7155 treatment groups, whereas there was no apoptotic cells in the control group. The survival periods in treated groups were significantly longer than that in the control group（P〈0.01）, and that of the high-dose group was longer than that of the low-dose group （P〈0.01）. The toxicity of ZD7155 was not apparent. Conclusion： ZD7155 can inhibit the growth of pancreatic cancer in vivo through disturbing tumor angiogenesis and inducing tumor cell apoptosis; it may possibly serve as a safe and effective agent for treatment of pancreatic cancer.