二甲双胍联合顺铂对人肺癌裸鼠移植瘤治疗作用的研究

Effects of metformin and cisplatin on human lung cancer xenograft in nude mice

目的研究二甲双胍联合常用的化疗药物顺铂对于人肺癌裸鼠移植瘤的抑瘤作用及对生存素（Survivin）、基质金属蛋白酶-2（MMP-2）和Ki67分子表达的影响，致力于探索治疗肺癌的新的有效药物。方法建立肺癌裸鼠移植瘤模型，将裸鼠随机分为二甲双胍组、顺铂组、二甲双胍联合顺铂组及对照组，给药42d后，处死动物，留取肿瘤组织，免疫组织化学法及实时荧光定量PCR法检测肿瘤组织中Survivin、MMP2和Ki67蛋白及mRNA的表达。结果二甲双胍组、顺铂组和二甲双胍联合顺铂组抑瘤率分别为28．97％、35．34％和54．65％。与对照组比较，顺铂组及二甲双胍联合顺铂组Survivin、MMP-2和Ki67蛋白及mRNA表达水平均降低（P值均〈0．05），二甲双胍组MMP-2蛋白及mRNA表达水平降低（P值均〈0．05）；与二甲双胍组、顺铂组比较，二甲双胍联合顺铂组Survivin、MMP2和Ki67蛋白及mRNA表达水平均降低（P值均〈0．05）。结论二甲双胍组可抑制MMP2的表达，顺铂组及二甲双胍联合顺铂组均可抑制Survivin、MMP-2和Ki67的表达，二甲双胍和顺铂联合应用可以增强抗肿瘤的疗效。

Objective This study is designed to evaluate the effects of metformin combined with eisplatin on tumor growth, expressions of Survivin, matrix metalloproteinase-2 （MMP-2）, and Ki67 in lung cancer xenograft on nude mice, to potentially develop new effective drugs for the treatment of lung caner. Methods Human lung cancer xenograft study model was established. The nude mice were randomly divided into metformin-treated group, cisplatin-treated group, metformin combined with eisplatin treated group and control group. Forty-two days after administration, all the nude mice were sacrificed and tumor tissues were sampled. The expressions of Survivin,MMP-2 ,and Ki67 proteins in the tumor tissues were detected by immumohistochemical method. The expressions of Survivin, MMP-2, and Ki67 mRNA in the tumor tissue were detected by florescent real-time quantitative PCR. Results The tumor inhibition rate in metformin-treated group, cisplatin-treated group, and metformin combined with cisplatin-treated group was 28.97%, 35.34%, and 54. 65%, respectively. The expressions of Survivin, MMP-2,and Ki67 protein and mRNA in cisplatin-treated group and metformin combined with cisplatin treated group were lower than those in control group （all P 〈20.05）. Compared with control group, the expressions of MMP-2 protein and mRNA in metformin-treated group were reduced （all P 〈 0.05）. Compared with metformin-treated group and cisplatin-treated group, the expressions of Survivin, MMP 2, and Ki67 protein and mRNA in metformin combined with cisplatin-treated group were reduced （all P〈0.05）. Conclusions Metformin could inhibit MMP 2 expression. Cisplatin or metformin combined with cisplatin can inhibit the expressions of Survivin, MMP 2, and Ki67. Combination drug of metformin and cisplatin can enhance the anti-tumor efficacy.