胰岛素样生长因子1受体反义寡核苷酸对人肝癌裸鼠原位瘤抑制作用及血液指标的影响

Antisense oligonucleotide against insulin-like growth factor I receptor inhibits tumor growth in human hepatocellular carcinoma orthotopic implantation models and its influence on the blood indicators in nude mice in vivo

目的探讨胰岛素样生长因子1受体反义寡核苷酸(IGF-1R ASODN)对人肝癌裸鼠原位瘤生长的抑制作用及对裸鼠血液指标的影响。方法本研究分3次实验,每次构建40只人肝癌原位移植瘤模型并分为生理盐水对照组、IGF-1R ASODN[75、50、25 mg/(kg·d)]3个剂量组及5-氟尿嘧啶(5-Fu)对照组,另取8只非荷瘤裸鼠设为对照组。各组荷瘤裸鼠静脉给药25次,实验结束后进行肝肿瘤体积、重量测量,计算抑瘤率,病理组织学检查,3次实验分别检测裸鼠血液的甲胎蛋白(AFP)、血常规、生化指标。结果IGF-1R ASODN各剂量组肝肿瘤体积和重量均小于生理盐水对照组,其中75 mg/(kg·d)组抑瘤率分别为76.36%、71.81%、78.81%,50 mg/(kg·d)组抑瘤率分别为55.65%、61.74%、63.58%,25 mg/(kg·d)组抑瘤率分别为47.72%、50.34%、54.30%。IGF-1R ASODN各剂量组肝肿瘤有不同程度的坏死及纤维组织增生。IGF-1R ASODN各剂量组AFP均低于生理盐水对照组(P<0.05),IGF-1R ASODN 75 mg/(kg·d)组血小板(PLT)低于正常对照组(P<0.05),IGF-1R ASODN 75 mg/(kg·d)组及50 mg/(kg·d)组谷氨酸(GLU)高于正常对照组(P<0.05),IGF-1R ASODN各剂量组白细胞(WBC)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、总胆红素(TBIL)、尿素氮(BUN)、总蛋白(TP)、肌酐(CR)与正常对照组比较差异无统计学意义(P>0.05)。结论IGF-1R ASODN是一种高效、低毒的抗肝癌生物学药物。

Objective To investigate the inhibitory effect of antisense oligonucleotide against insulin-like growth factor 1 receptor (IGR-1R) on tumor growth in human hepatocellular carcinoma orthotopic implantation models and its influence on the blood indicators in nude mice. Methods We did the experiment 3 times, and 40 models for each time were divided into 5 groups randomly: NS control group, three IGF-1R antisense oligdeoxynucleotides (ASODN)[75, 50, 25 mg/(kg·day)] groups and 5-fluorouracil (5-Fu) control group. Eighty nude mice served as normal control group. The agents were given for 25 times through intravenous injection in human hepatocellular carcinoma orthotopic implantation models. When the experiment was over, the volume and weight of tumor were measure, the inhibitory rate of tumor growth was calculate, and the pathomorphological change was examined. Alpha fetal protein (AFP), routine blood test and biochemical indexes were determined in three experiments respectively. Results The average volume and weight of tumor in IGF-1R ASODN group was significantly reduced as compared with those in NS control group. The inhibitory rate of tumor growth in 75 mg/(kg·day) IGF-1R APSODN group in three experiments were 76.36%, 71.81% and 78.81%, 55.65%, 61.74% and 63.58% in 50 mg/(kg·day) group, and 47.72%, 50.34% and 54.30% in 25 mg/(kg·day) group respectively. Large piece of necrosis and fibrosis could be seen under a light microscope in IGF-1R ASODN groups. AFP in IGF-1R ASODN groups was lower (P<0.05) than in NS control group, PLT in IGF-1R ASODN group [75 mg/(kg·day)] was lower than in NS control group (P<0.05), and GLU in IGF-1R ASODN group [75 mg/(kg·day) and 50 mg/(kg·day)] was higher than in normal control group (P<0.05). There was no significant difference between IGF-1R ASODN group and normal control group in other blood indicators. Conclusion IGF-1R ASODN is an anti-hepatoma biological agent with high efficiency and low side-effect.