重组人血管内皮抑素联合紫杉醇不同时序给药降低肺癌移植瘤小鼠血清中VEGF和HIF-1α的水平及其意义  

Reducing effects of recombinant human endostatin combined with paclitaxel under different delivery order on expressions of serum VEGF and HIF-1α in lung cancer xenografts in mice

作　　者：李萌[1] 丁瑞麟 文庆莲[1] 

机构地区：[1]泸州医学院附属医院肿瘤科,四川泸州646000

出　　处：《肿瘤》2016年第3期264-271,共8页Tumor

基　　金：四川省科学技术厅科研专项资金计划项目(编号:2014-10-146)~~

摘　　要：目的：研究重组人血管内皮抑素（recombinant human endostatin,rhendostatin）联合紫杉醇（paclitaxel,PTX）不同时序给药对肺癌移植瘤小鼠血清中血管内皮生长因子（vascular endothelial growth factor,VEGF）和缺氧诱导因子1α（hypoxia inducible factor-1α,HIF-1α）水平的影响及其意义,并探讨rh-endostatin联合PTX给药的最佳时序。方法 ：建立肺癌Lewis细胞的C57/BL小鼠皮下移植瘤模型,并随机分为对照组（腹腔注射0.9%Na Cl,第1~14天）、单药PTX组（腹腔注射PTX,第1天）、单药rh-endostatin组（腹腔注射rh-endostatin,第1~14天）、联合组1[腹腔注射rh-endostatin（第1~14天）＋PTX（第1天）]、联合组2[腹腔注射rh-endostatin（第1~14天）＋PTX（第4天）]和联合组3[腹腔注射rh-endostatin（第1~14天）＋PTX（第7天）]。各组给药后,动态测量小鼠移植瘤体积,免疫组织化学法检测移植瘤组织中微血管密度（microvascular density,MVD）以及可反映微血管周细胞量的α平滑肌肌动蛋白（α-smooth muscle actin,α-SMA）表达水平,ELISA法检测小鼠血清中VEGF和HIF-1α的水平,高效液相色谱法检测移植瘤组织中PTX的浓度。结果 ：从用药的第2天开始,rh-endostatin单药组及各联合组血清中VEGF水平均明显降低（P值均〈0.05）;从用药的第5天开始,rh-endostatin单药组及各联合组血清中HIF-1α水平也明显降低（P值均〈0.05）;在用药的第5天及第8天,rh-endostatin单药组及各联合组肿瘤组织中MVD较对照组明显降低（P值均〈0.05）,而α-SMA表达水平较对照组明显升高（P值均〈0.05）;在3个联合组中,联合组2与对照组的MVD以及VEGF、HIF-1α和α-SMA表达水平差异最明显（P值均〈0.05）。联合组2的小鼠移植瘤组织中PTX浓度明显高于另外2个联合组（P值均〈0.05）,移植瘤体积也明显小于另外2个联合组（P值均〈0.05）。结论 ：血清VEGF和HIF-1α水平可作为监测肿瘤微血管正常化的Objective：To study the effects of recombinant human endostatin（rh-endostatin） combined with paclitaxel（PTX） under different delivery order on the expression levels of serum vascular endothelial growth factor（VECF） and hypoxia-inducible factor-1α（HIF-1α） in lung cancer xenografts in mice,and to investigate the optimal delivery order of rh-endostatin combined with PTX.Methods：Subcutaneous Lewis lung cancer xenograft model of C57/BL mice was established,then the mice were randomly divided into control group（intraperitoneal injection with0.9%NaCI,dl-14）,PTX group（intraperitoneal injection with PTX,d1）,rh-endostatin group（intraperitoneal injection with rh-endostatin,dl-14）,combination group 1[intraperitoneal injection with rh-endostatin（d1-14） and PTX（d1）],combination group 2[intraperitoneal injection with rh-endostatin（d1-14） and PTX（d4）],and combination group 3[intraperitoneal injection with rh-endostatin（d1-14） and PTX（d7）].After drug administration,the volume of xenograft tumor in different groups was measured dynamically,the microvascular density（MVD） and the expression level of a-smooth muscle actin（a-SMA） in xenograft tumor tissues were detected by immunohistochemistry,the serum VECF and HIF-1α levels were detected by enzyme-linked immunosorbent assay（ELISA）,as well as the concentration of PTX in xenograft tumor tissues was detected by high-performance liquid chromatography（HPLC）.Results：Since the second day of drug administration,the serum VECF levels in rh-endostatin group and three combination groups were significantly lower than that in the control group（all P 〈 0.05）.Since the fifth day of drug administration,HIF-1α levels in rh-endostatin group and three combination groups were also decreased significantly（all P 〈 0.05）.On the fifth and eighth days of drug administration,MVDs in rh-endostatin group and 3 combination groups were lower than that in the control group（all P 〈 0.05）,while the expression level of a-S

关 键 词：肺肿瘤 内皮抑素类 紫杉醇 血管内皮生长因子 缺氧诱导因子1 Α亚基 

分 类 号：R734.2[医药卫生—肿瘤]