三氧化二砷抑制宫颈癌生长的体内实验研究

The inhibitory effect of arsenic trioxide on the growth of cervical cancer in vivo

目的探讨三氧化二砷(arsenic trioxide,ATO,As_2O_3)对宫颈癌Hela细胞裸鼠移植瘤体内作用及其机制。方法建立裸鼠宫颈癌移植瘤模型,用低浓度As_2O_3[2mg/(kg·d)],高浓度As_2O_3[[5 mg/(kg·d)],顺铂(DDP)[3 mg/(kg·d)1及0.9%NaCl腹腔连续给药10 d,观察移植瘤的生长情况和抑瘤率,药物对裸鼠体重、肝肾组织的影响。通过流式细胞仪检测瘤细胞凋亡率,应用免疫组化方法检测p38和Caspase-3的表达。结果低浓度As_2O_3高浓度As_2O_3及DDP组的抑瘤率分别为31.48%,33.61%和53.11%,高浓度As_2O_3和DDP组的抑瘤率与阴性对照组的差异有统计学意义(P<0.05),DDP组药物的毒副作用大。两种浓度As_2O_3引起的细胞凋亡率明显高于阴性对照组(P<0.05)。P-P38和Caspase-3蛋白在As_2O_3治疗组的表达明显高于阴性对照组(P<0.05),且二者呈正相关(r=0.5164,P=0.01)。结论 As_2O_3能明显抑制宫颈癌移植瘤的生长,且毒副作用明显小于DDP,其抑癌机制之一为诱导肿瘤细胞凋亡。

[ Objective ] To study the inhibitory effect of arsenic trioxide （ATO, As2O3） on the tumor growth of Hela cervical cancer cell xenografts in nude mice and its mechanism. [ Methods ] Human cervical cancer xenograft model was established in nude mice. The tumor-bearing nude mice were randomly divided into ATO low dose group [2 mg/（kg.d）], ATO high dose group [5 mg/（kg.d）], DDP positive control group [3 mg/（kg.d）], saline negative control group （0.9%NaCl 0.2 ml/d）. The drugs were administered intraperitoneaHy for 10 consecutive days. The growth rate of tumor, tumor inhibition rate and pathology feature of liver and kidney were oberserved. Cell apoptosis was evaluated by flow cytometry and ultramicrostructure was oberserved under electron microscope. Immunohistochemistry was used to measure the expression of p-p38 and caspase-3. [ Results ] ATO low and high dose group and DDP positive control group inhibited tumor volume respectively by 31.48%, 33.61% and 53.11%. The inhibited effect of ATO [5 mg/（kg.d）] was similar with DDP [3 mg/（kg.d）], but the toxic effect of DDP was higher than ATO. The apoptosis rate of ATO group was obviously higher than negative control group. The expression of p-p38 and easpase-3 were higher than that in negative control group （P 〈0.05） and was positively correlated with each other. [ Conclusion] ATO can inhibit the growth of cervical cancer cells in vivo, and its toxicity effect is lower than that of DDP. The mechanism of ATO＇s inhibition on the growth of tumor is to induce apoptosis of tumor ceils.