As_2O_3对人子宫肉瘤裸鼠移植瘤抑制作用及其机制

INHIBITORY EFFECT AND MECHANISM OF ARSENIC TRIOXIDE AGAINST HUMAN UTERINE SARCOMA TRANSPLANTED INTO NUDE MICE

目的探讨三氧化二砷(As_2O_3)对人子宫肉瘤裸鼠移植瘤的抑制作用及其机制。方法裸鼠40只,建立子宫肉瘤皮下移植瘤模型,随机分为As_2O_3低、中、高剂量组及生理盐水(NS)组、异环磷酰胺(IFO)组5组,每天将相应剂量(1.0、2.5、5.0mg/kg)As_2O_3、NS及IFO腹腔注射入裸鼠体内,连用10d。停药后处死裸鼠,取肿瘤组织称瘤质量,比较各组抑瘤率;同时检测各组肿瘤组织细胞凋亡率及半胱氨酸天冬氨酸蛋白水解酶(caspase-3)与磷酸化细胞外信号调节激酶(p-ERK)基因的表达。结果 As_2O_3各剂量组裸鼠一般情况可,与NS组裸鼠差别不大,IFO组裸鼠一般状态不佳。As_2O_3各剂量组及IFO组瘤质量均小于NS组,As_2O_3高剂量组及IFO组瘤质量小于As_2O_3中、低剂量组,差异有显著性(F=108.368,P<0.05)。As_2O_3各剂量组及IFO组细胞凋亡率均高于NS组,As_2O_3各剂量组细胞凋亡率高于IFO组,As_2O_3高剂量组细胞凋亡率高于中、低剂量组,差异有显著性(F=778.240,P<0.05)。As_2O_3各剂量组细胞caspase-3基因表达高于NS组及IFO组,差异有显著性(F=30.670,P<0.05)。As_2O_3高剂量组细胞p-ERK基因的表达阳性率低于NS组,差异有显著性(Z=-2.063,P<0.05)。结论 As_2O_3对人子宫肉瘤裸鼠皮下移植瘤细胞增殖有抑制作用,并可能通过上调细胞中caspase-3基因表达促进细胞凋亡,而通过下调p-ERK基因表达影响信号传导通路抑制肿瘤生长。

Objective To investigate the inhibitory effect and mechanism of arsenic trioxide （As2Oa） against human uterine sarcoma transplanted into nude mice. Methods Human uterine sarcoma was subcutaneously transplanted into 40 nude mice. Those mice were randomly divided into low , medium , and high dose As203 groups, normal saline （NS） group, and ifos- famide （IFO） group. Those mice received intraperitoneal injection of different doses of As2O3, IFO, or NS for 10 consecutive days and were sacrificed after drug withdrawal. Tumor tissues were collected for the measurement of tumor weight and between group comparison of tumor inhibition rate. The apoptosis rate and expression of caspase-3 and phosphorylated extracellular signal-regula- ted kinase （p-ERK） in tumor tissues were compared between different groups. Results As2 O3-treated mice, similar to those in the NS group, had better health conditions than those in the IFO group. The As2O3 and IFO groups had lower tumor weight than the NS group. The high-dose As20a group and the IFO group had significantly lower tumor weight than the medium-dose As2 O2 group and the low-dose As20a group （F = 108.368 ,P〈〈0.05）. The As2 O3 groups had the highest apoptosis rates, followed by the IF（） group and the NS group; the high-dose As2O3 group had a significantly higher apoptosis rate than the medium-dose As2Oa group and the low-dose As203 group （F=778. 240, P d0.05）. The As203 groups had significantly higher gene expression of caspase 3 than the NS group and the IFO group （F=30.670,P〈O.05）. The high-dose AszOa group had a significantly lower gene expression rate of p-ERK than the NS group （Z= -2.063,P〈0.05）. Conclusion As2Oa can inhibit the proliferation of human uterine sarcoma subcutaneously transplanted into nude mice. The inhibitory effect may result from enhanced apoptosis by upregu- lated caspase-3 gene expression and repressed tumor growth by downregulated p ERK gene expression and signaling pathway.