三氧化二砷抗肝癌作用及其肾毒性作用的实验研究

Experimental study on antitumor effect and renal toxicity of arsenic trioxide during treatment of hepatocellular carcinoma

目的 研究三氧化二砷 (As2 O3)抗肝癌作用及其对肾脏的毒副作用并探讨其作用机制。方法 二乙基亚硝胺灌胃制备大鼠肝癌模型。以As2 O3或顺铂注射于大鼠腹腔 ,第 7、1 4、2 8天获取肝癌结节 ,光、电镜下观察肝癌细胞形态学变化 ,流式细胞仪检测凋亡及细胞动力学变化。第 2 8天获取肾脏 ,光镜下观察肾脏组织形态学变化 ,免疫组织化学SP法检测bcl 2、增殖细胞核抗原(PCNA)表达变化。结果 As2 O3诱导大鼠肝癌细胞凋亡 ,出现典型形态学改变 ;引起肝癌细胞凋亡率上升 ,中剂量组 (1mg/kg体重 )显著上升 ,明显高于顺铂组 (P =0 .0 0 0 )。顺铂组大鼠肾脏(4/ 7)镜下出现肾小管上皮细胞浊肿、变性 ,集合管内蛋白管型出现 ,而砷剂组无明显改变 (P =0 .0 1 3) ;砷剂组肾小管上皮细胞bcl 2表达增加 (P =0 .0 0 5) ,PCNA标记指数无明显改变 ,顺铂组PCNALI明显升高 (P =0 .0 0 1 )。结论 As2 O3可诱导大鼠肝癌细胞凋亡 ,且优于顺铂 ;与顺铂相比 。

Objective To study antitumor effect and renal toxicity of arsenic trioxide (As 2O 3) during treatment of hepatocellular carcinoma (HCC),and investigate the possible mechanism.Methods Wistar rats were fed with diethylnitrosamine(DEN)to induce HCC,then treated with As 2O 3 or cisplatin intraperitonealy.The histological changes in liver tissue were observed under light and electron microscope on 7,14 and 28 day after drug administration,and apoptosis or cellular dynamic parameters were observed by flow cytometry.The morphological changes in kidneys were observed under microscope on 28 day,and the changes of bcl 2 or PCNA were investigated by using S P immunohistochemical staining.Results Typical features of apoptosis were observed in As 2O 3 treated groups.Compared with cisplatin,As 2O 3 was more efficient in inducing apoptosis when the dose was appropriate(1?mg/kg).No evident morphological abnormalities were found in As 2O 3 treated groups.However,apparent pathological changes of renal tubule epithelial cells were observed in cisplatin treated group (4/7,P=0.013).The positive rate of bcl 2 in renal tubule epithelial cells was higher in As 2O 3 treated groups than that in cisplatin treated group(P= 0.005), while PCNA labeling index in cisplatin treated group was much higher than that in As 2O 3 treated groups(P= 0.001). Conclusion These data demonstrate that As 2O 3 induces apoptosis,and it is more efficient than cisplatin.Compared with cisplatin,As 2O 3 causes no evident renal damage.