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目的:观察计算机辅助药物设计合成的特异性多肽p166结合顺铂对人结肠癌裸鼠移植瘤的抑制作用及毒副反应,并探讨其作用机制。方法:建立人结肠癌细胞株HCT-116裸鼠皮下移植瘤模型,随机分为生理盐水组、顺铂组(1 mg/kg)和p166结合顺铂组(4 mg/kg,其中顺铂浓度为1 mg/kg)。连续腹腔注射给药10 d,给药期间测瘤体体积计算抑瘤率,第11天处死裸鼠,采血测肝肾功能,剥离瘤体标本HE染色,采用免疫组化法检测凋亡因子Bcl-2、Bax、Cyt C和Caspase-3的表达。结果:p166结合顺铂组和顺铂组,抑瘤率分别为56.98%和41.96%。p166结合顺铂组血清BUN、Cr、ALT和AST水平均低于顺铂组,其中Cr、ALT和AST水平与顺铂组比较差异有统计学意义,P<0.05。免疫组化结果显示,与顺铂组比较,p166结合顺铂组Bcl-2蛋白表达减少,Bax、Cyt C和Caspase-3蛋白表达增强。结论:p166结合顺铂对HCT-116人结肠癌裸鼠移植瘤具有显著抑制作用,且能减少顺铂对裸鼠肝肾功能的影响。其机制可能与p166结合顺铂后能增加顺铂穿透肿瘤细胞胞膜的能力有关。
OBJECTIVE: To observe the inhibitory effect and toxicity of the specific peptide p166 combined with cisplatin, which was designed and synthesized by computer-aided drug, on human colon carcinoma xenografts in nude mice and to explore its mechanism. Methods: Human colon cancer cell line HCT-116 subcutaneously transplanted into nude mice was established and randomly divided into normal saline group, cisplatin group (1 mg / kg) and p166 combined with cisplatin group (4 mg / kg, 1 mg / kg). The mice were sacrificed on the 11th day, and the liver and kidney were collected for blood test. HE staining was performed to dissect the tumor and immunohistochemistry was used to detect the expression of Bcl-2 -2, Bax, Cyt C and Caspase-3 expression. Results: The inhibition rates of p166 combined with cisplatin and cisplatin were 56.98% and 41.96% respectively. The serum levels of BUN, Cr, ALT and AST in p166 combined with cisplatin group were lower than those in cisplatin group, and there was significant difference in the levels of Cr, ALT and AST between cisplatin group and cisplatin group (P <0.05). The results of immunohistochemistry showed that compared with the cisplatin group, the expression of Bcl-2 protein, Bax, Cyt C and Caspase-3 protein increased in p166 and cisplatin group. Conclusion: The combination of p166 and cisplatin has a significant inhibitory effect on HCT-116 human colon carcinoma xenografts in nude mice and can reduce the effect of cisplatin on liver and kidney function in nude mice. The mechanism may be related to the combination of p166 and cisplatin can increase the ability of cisplatin to penetrate the tumor cell membrane.