【摘要】 目的?通过体内和体外实验,探讨金雀异黄素(Gen)与5-氟尿嘧啶(5-FU)联用对肝癌的化疗增敏效果。方法体外实验中根据干预方法分别将人肝癌细胞株Bel-7404、SMMC-7721和HepG2分为溶剂对照(NC)组、10 μmol/L Gen处理组、2 μmol/L 5-FU处理组及Gen+5-FU联合处理组,利用CCK-8法及流式细胞技术研究Gen与5-FU联用对肝癌细胞增殖和凋亡的影响。体内实验分别构建Bel-7404 肿瘤细胞系异种移植(CDX)和Liver-0117人源肿瘤组织异种移植(PDX)裸小鼠模型,然后将荷瘤裸小鼠模型分为4组:NC组、Gen处理组、5-FU处理组和Gen+5-FU联合处理组,观察不同剂量Gen与5-FU单独或联合处理肝癌模型对肿瘤生长的影响。结果在处理24、48、72 h后,Gen+5-FU联合处理组Bel-7404、SMMC-7721和HepG2细胞增殖率均低于NC组、Gen处理组及5-FU处理组(P均<0.01);处理72 h后Gen+5-FU联合处理组Bel-7404、SMMC-7721和HepG2细胞凋亡率均高于NC组、Gen处理组及5-FU处理组(P均<0.01)。对于Bel-7404荷瘤裸小鼠,给药28 d后NC组、Gen(15 mg/kg)处理组、5-FU(30 mg/kg)处理组、Gen(15 mg/kg)+5-FU(20 mg/kg)联合处理组肿瘤相对体积(RTV)分别为15.35±2.92、17.51±3.11、12.93±4.88、13.67±3.54,组间差异无统计学意义(F=1.822,P>0.05);提高Gen剂量至40 mg/kg干预21 d后,Gen(40 mg/kg)处理组的RTV低于NC组(9.73±5.85 vs 17.54±5.06),差异有统计学意义(P<0.05)。对于PDX模型Liver-0117荷瘤裸小鼠,给药18 d后,Gen(15 mg/kg)+5-FU(20 mg/kg)联合处理组的RTV低于5-FU(30 mg/kg)处理组(12.64±0.92 vs 18.76±0.68),差异有统计学意义(P<0.05),相对肿瘤抑制率(T/C)为 0.576。结论 Gen与5-FU联用在体外表现出较好的化疗增敏效果,但对于不同荷瘤裸小鼠模型其增敏效果不同。更多还原

【Abstract】 Objective To investigate the chemosensitization effects of genistein (Gen) combined with 5-fluorouracil(5-FU) on hepatocellular carcinoma in vitro and in vivo.Methods In the in vitro experiments,human hepatocellular carcinoma cell lines (Bel-7404,SMMC-7721 and HepG2) were used in negative control (NC) group,Gen group (10μmol/L),5-FU group (2μmol/L) as well as Gen+5-FU group according to the intervention methods.The effects of Gen combined with5-FU on the proliferation and apoptosis of hepatocellular carcinoma cells were analyzed by cell counting kit 8 (CCK-8) method and flow cytometry.Bel-7404 cell line-derived xenograft (CDX) and Liver-0117 patient-derived xenograft (PDX) mouse models were constructed in vivo.Then the tumor-bearing mouse models were divided into 4 groups:NC group,Gen group,5-FU group and Gen+5-FU group.The effects of different treatment methods on tumor growth were observed.Results The proliferation rates of Bel-7404,SMMC-7721 and HepG2 cells in the Gen+5-FU group were significantly lower than those in the Gen group and 5-FU group (all P<0.01) after 24,48 and 72 h of treatment;the average apoptosis rates of these cells were significantly higher in the Gen+5-FU group than in the NC group,Gen group and 5-FU group after 72 h of culture (all P<0.01).The relative tumor volumes (RTVs) of the Bel-7404 CDX tumor-bearing mice in the NC group,Gen (15 mg/kg)group,5-FU (30 mg/kg) group and Gen (15 mg/kg)+5-FU (20 mg/kg) group 28 d after administration were 15.35±2.92,17.51±3.11,12.93±4.88 and 13.67±3.54,respectively,showing no significant difference (F=1.822,P>0.05);after increasing the dose of Gen to 40 mg/kg for 21 d,the RTV of the Gen (40 mg/kg) group was significantly lower than that of the NC group (9.73±5.85 vs 17.54±5.06,P<0.05).The RTV of the Liver-0117 PDX tumor-bearing mice in the Gen (15 mg/kg)+5-FU(20 mg/kg) group 18 d after administration was significantly lower than that in the 5-FU (30 mg/kg) group (12.64±0.92 vs18.76±0.68,P<0.05),and the ratio of RTV between treatment group and control group was 0.576.Conclusion Gen combined with 5-FU shows good chemosensitization effects in vitro,which are varied on different models of tumor-bearing mice.更多还原