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目的探讨不同剂量As2O3对Vx2软组织肿瘤细胞凋亡及血管内皮细胞生长因子(VEGF)表达的影响及As2O3抗肿瘤的作用机制。方法32只大白兔皮下软组织内肿瘤种植2w后,随机分为实验组和对照组。实验组根据As2O3用药量不同分为1、2、4mg·kg-1·d-13个亚组,每组8只,对照组注射生理盐水,连续给药7d,停药后继续观察3w后处死大白兔,采用MRI测量治疗前后肿瘤最大直径,分别于给药前及处死前行肝肾功能检查,检测As2O3对肝肾毒性作用;采用原位末端标记法(TUNEL法)检测肿瘤细胞的凋亡指数及VEGF染色法观测As2O3抑制肿瘤细胞VEGF表达的程度。结果MRI显示对照组肿瘤随观察时间延长呈持续增大;实验组随着用药剂量增加,肿瘤增长缓慢(与对照组相比P<0.05);1、2mg·kg-1·d-1亚组与4mg·kg-1·d-1亚组组间差异较明显(P<0.05),1mg·kg-1·d-1与2mg·kg-1·d-1亚组组间差异不明显(P>0.05)。给药前及处死前行耳缘静脉取血,测定ALT、AST、BUN、Cr水平,给药前各组间差异不明显(P>0.05),处死前基本恢复正常,组间差异不显著(P>0.05)。HE染色显示对照组肿瘤周围组织浸润明显,实验组周围组织浸润不明显;TUNEL法对照组肿瘤坏死周围细胞凋亡与治疗组比较差异显著(P<0.05),1、2mg·kg-1·d-1与4mg·kg-1·d-1亚组组间差异较明显(P<0.05),1mg·kg-1·d-1与2mg·kg-1·d-1亚组组间差异不明显(P>0.05)。VEGF染色法显示肿瘤细胞内VEGF表达随药物浓度增加而减少,与对照组相比差异显著(P<0.05)。结论经腹腔注射As2O3能够控制Vx2软组织肿瘤增长,同时诱导肿瘤细胞凋亡及抑制肿瘤血管生成,并与剂量相关,其对肝肾功能毒性作用不明显。
Objective To investigate the effects of different doses of As2O3 on Vx2 soft tissue tumor cell apoptosis and the expression of vascular endothelial growth factor (VEGF) and the anti-tumor mechanism of As2O3. Methods Twenty-two rabbits were subcutaneously injected with subcutaneous soft tissue for 2 weeks and then randomly divided into experimental group and control group. The experimental group was divided into 1, 2, 4 mg · kg-1 · d-13 subgroups according to the dosage of As2O3, and each group had 8 rats in each group. The control group was injected with normal saline for 7 days. The maximum diameter of the tumor before and after treatment was measured by MRI in rabbits. Liver and kidney function tests were performed before administration and before sacrifice, and the effect of As2O3 on hepatotoxicity was assayed. Apoptosis of tumor cells was detected by TUNEL method Index and VEGF staining were used to observe the extent of As2O3 inhibiting VEGF expression in tumor cells. Results The MRI showed that the tumors in the control group continued to increase with the prolongation of the observation time. The tumor volume increased slowly in the experimental group as compared with that in the control group (P <0.05 compared with the control group); in the 1, 2 mg · kg-1 · d-1 subgroup And 4 mg · kg-1 · d-1 subgroups were significantly different (P <0.05). The difference between 1 mg · kg-1 · d-1 and 2 mg · kg-1 · d-1 subgroups was not significant P> 0.05). Blood samples were taken from the ear vein before administration and before sacrifice. The levels of ALT, AST, BUN and Cr were measured before treatment and there was no significant difference among the groups before administration (P> 0.05) P> 0.05). Hematoxylin-eosin staining showed that the infiltration of tumor tissue around the tumor in the control group was obvious, and the infiltration of tissue around the experimental group was not obvious. The apoptosis of tumor surrounding the tumor necrosis in the TUNEL group was significantly different from that in the treatment group (P <0.05), 1, 2 mg · kg-1 · d 1 and 4mg · kg-1 · d-1 subgroups were significantly different (P <0.05). The difference between 1mg · kg-1 · d-1 and 2mg · kg-1 · d-1 subgroups was not significant Obviously (P> 0.05). VEGF staining showed that the expression of VEGF in tumor cells decreased with the increase of drug concentration, which was significantly different from the control group (P <0.05). Conclusion Intraperitoneal injection of As2O3 can control Vx2 soft tissue tumor growth, induce tumor cell apoptosis and inhibit tumor angiogenesis at the same time, and dose-dependently, and its toxic effect on liver and kidney function is not obvious.