端粒酶抑制剂联合化疗对胃癌的作用

Effects of telomerase inhibitors combined with chemotherapy on gastric cancer xenograft in mice

目的 探讨端粒酶抑制剂对动物在体肿瘤的治疗价值及端粒酶抑制剂能否增加化疗药物的治疗效果。方法 应用端粒酶抑制剂 [齐多夫啶 (AZT) /(kg·d) ]联合化疗药 5 氟尿嘧啶 (5 Fu)治疗BALB/c小鼠移植性胃癌 (SGC 790 1) ,观察其对抑瘤率、肿瘤端粒酶的表达及其肿瘤细胞凋亡的影响。结果 5 Fu、AZT、5 Fu +AZT抑瘤率分别为 11.65 %、2 8.15 %、42 .75 % ,5 Fu、AZT均能抑制肿瘤生长 (P <0 .0 5 ) ,并且AZT与 5 Fu联用明显优于两者单独使用 (P <0 .0 5 )。末端标记法检测肿瘤细胞凋亡指数分别为 (7.17± 0 .3 4) %、(19.3 5± 1.2 3 ) %、(2 3 .49± 2 .41) % ,流式细胞分析示其凋亡率分别为 (9.3 8± 3 .16) %、(17.3 4± 2 .0 4) %、(2 5 .74± 1.0 7) %。肿瘤端粒酶活性检测显示各组端粒酶阳性率分别为 42 .75 %、3 7.5 0 %、12 .5 0 % ,与对照组 87.5 0 %对比 ,5 Fu、AZT均有减少肿瘤端粒酶活性的作用 (P <0 .0 5 ) ,且AZT与 5 Fu具有协同作用。结论 5 Fu及AZT均能抑制小鼠胃癌SGC790 1细胞的生长及降低其端粒酶活性、诱导细胞凋亡 ,AZT与 5 Fu联用有相加作用 ,抑制端粒酶活性是癌症治疗的一个新靶点。

ObjectiveTo evaluate the treatment value of telomerase inhibitor for animal tumor in vivo.MethodsThe telomerase inhibitors (azidothymidine AZT 300 mg·kg -1·d -1) and chemotherapy agent (5-Fu,0.5 mg ip) were used to treat gastric cancers (SGC7901) xenograft in BALA/c mice.Their influence on tumor weight,telomerase expression and apoptotic indices (AI) were evaluated.Telomerase activity was examined by a PCR-based telomeric repeat amplification protoco (TRAP) coupled with ELISA.AI were examined by terminal deoxynueleotidyl transferase-mediated deoxyuridime triphosphate fluorescence nick end labeling (TUNEL) method and flow cytometry analysis (FCAS).Morphological changes were observed under electron microscopy.ResultsThe tumor weight of mice was reduced by 11.65%,28.15% and 42.75% in 5-Fu,AZT and AZT combined with 5-Fu respectively.Combined model (AZT+5-Fu) was more effective than others used alone ( P <0.05).AI determined by TUNEL were (7.17±0.34)%,(19.35±1.23)%,and (23.49±2.41)% respectively.AI determined by FCAS were (9.38±3.16)%,(17.34±2.04)% and (25.74±1.07)% respectively.They indicated that both 5-Fu and AZT could induce apoptosis,and AZT combined with 5-Fu was superior to AZT or 5-Fu used alone ( P <0.05).The positive rates of telomerase activity were 42.75% in 5-Fu,37.50% in AZT,and 12.50% in 5-Fu +AZT,suggesting both 5-Fu and AZT could decrease the activity of tumor telonerase ( P <0.05) and AZT combined with 5-Fu had an additive effect ( P <0.05).ConclusionBoth AZTand 5-Fu are effective to treat gastric cancer SGC7901 through decreasing telomerase activity and reducing tumor weight,enhancing apoptosis.AZT can increase the chemotherapy sensitivity for SGC7901.