VEGF反义寡核苷酸与低分子肝素联合应用对小鼠Lewis肺癌生长和肺血栓栓塞症的影响

首都医科大学学报 ›› 2006, Vol. 27 ›› Issue (1): 38-42.

VEGF反义寡核苷酸与低分子肝素联合应用对小鼠Lewis肺癌生长和肺血栓栓塞症的影响

张予辉, 王辰, 张黎明, 翟振国, 庞宝森

首都医科大学附属北京朝阳医院呼吸内科北京呼吸疾病研究所

收稿日期:2005-12-16 修回日期:1900-01-01 出版日期:2006-02-24 发布日期:2006-02-24
通讯作者: 王　辰

Effect of VEGF Antisense Oligonucleotides Combined with Low Molecular Weight Heparin on Tumor Growth and Pulmonary Thromboembolism in Mice Lewis Lung Cancer

Zhang Yuhui, Wang Chen, Zhang Liming, Zai Zhenguo, Pang Baoshen

Department of Respiration, Beijing Chaoyang Hospital, Beijing Institute of Respiratory Medicine, Capital University of Medical Sciences

Received:2005-12-16 Revised:1900-01-01 Online:2006-02-24 Published:2006-02-24

摘要/Abstract

摘要： 目的探讨血管内皮细胞生长因子(VEGF)反义寡核苷酸(ASODN)与低分子肝素(LMWH)联合应用对小鼠Lewis肺癌生长、凝血及肺血栓栓塞症(PTE)的影响及其机制.方法复制Lewis肺癌模型小鼠40只,随机分为对照组、VEGF-ASODN组、VEGF错义寡核苷酸( MSODN)组、LMWH组及联合治疗组,每组8只,分别给予生理盐水、VEGF-ASODN、VEGF-MSODN、LMWH(法安明)及VEGF-ASODN+法安明皮下注射,隔日1次,共15次.检测皮下移植瘤的变化.应用免疫组织化学方法检测肿瘤组织微血管密度(MVD).应用酶联免疫吸附方法检测血浆中VEGF和凝血激活剂组织因子(TF)的质量浓度.应用组织HE染色方法检查肿瘤组织、心、肺、脑、肾、肝等组织脏器的血栓和栓塞情况.应用Western blot方法检查肿瘤组织VEGF和TF蛋白表达.结果 ASODN、LMWH和联合治疗组的抑瘤率分别为47.34%、27.31%和59.03%,这3组的抑瘤率和MVD与对照组和MSODN组相比差异均有统计学意义(P＜0.05). ASODN组和联合治疗组的血浆VEGF质量浓度分别为(9.66±1.02)ng/L、(9.39±2.26)ng/L,较对照组[(14.39±3.76)ng/L]显著降低(P＜0.05);LMWH组和联合治疗组血浆TF质量浓度分别为(20.00±1.26)ng/L、 (23.50±5.62)ng/L, 较对照组[(27.08±5.40)ng/L]显著降低(P＜0.05).对照组、ASODN组、MSODN组、LMWH组、联合治疗组PTE的发生率分别为37.5%、50.0%、37.5%、25.0%和25.0%;ASODN组肿瘤组织中VEGF蛋白表达较弱,而TF表达较强.结论 VEGF-ASODN和LMWH联合有协同抗肿瘤作用;但VEGF-ASODN有促凝作用,使PTE的风险增加,而LMWH可降低高凝倾向.

关键词: 血管内皮细胞生长因子, 低分子肝素, 肺肿瘤, 肺血栓栓塞症

Abstract: Objective To investigate the effect of vascular endothelial growth factor(VEGF) antisense oligonucleotides(ASODN) or/and low molecular weight heparin(LMWH) fragmin on tumor growth,coagulation,thrombosis and embolism in mice Lewis lung cancer.Methods 40 mice with Lewis lung cancer were randomly divided into five groups: control group,VEGF-ASODN group,VEGF mismatch sense oligonucleotides(MSODN) group,LMWH group,and combined group.Sodium chloride,VEGF-ASODN,VEGF-MSODN,fragmin,and VEGF-ASODN plus fragmin were given respectively(once every two days,15 times altogether).Volume and weight of subcutaneous tumors were measured;Microvessel density(MVD) in tumor mass was measured by imuunohistochemistry staining;Concentration of plasma VEGF and coagulation initiator tissue factor(TF) were detected by ELASA method;thrombosis and embolism were detected by tissue HE staining method;VEGF and TF protein level in tumor tissue were detected by Western blot assay.Results Tumor growth inhibitory rates of ASODN group,LMWH group,and combined group were 47.34%,27.31% and 59.03%,respectively.There was significant difference on tumor growth inhibitory rates and MVD between above three treated groups and control group as well as MSODN group(P<0.05).Mean concentration of plasma VEGF in ASODN group,combined group were(9.66±(1.02))ng/L,(9.39±2.26)ng/L which were lower than that of control group [(14.39±3.76)ng/L](P<0.05);Mean concentrationof plasma TF in LMWH(group,) combined group were((20.00)±(1.26))ng/L,((23.50)±(5.62))ng/L which were lower than that of control group [(27.08±5.40)ng/L](P<0.05).Pulmonary thromboembolism(PTE) was relatively common,rates of PTE in control group,ASODN group,MSODN group,LMWH group,combined group were 37.5%,50.0%,37.5%,25.0%,25.0%,respectively. In ASODN group,VEGF protein expression was lower,but TF protein expression was higher.Conclusion VEGF-ASODN combined with LMWH can enhance anti-tumor effect.VEGF-ASODN may exacerbate hypercoagulation so as that the risk to PTE increased.However LMWH may reduce the tendency of hypercoagulation.

Key words: vascular endothelial growth factor, low molecular weight heparin, lung neoplasm, pulmonary thromboembolism

中图分类号:

张予辉;王辰;张黎明;翟振国;庞宝森. VEGF反义寡核苷酸与低分子肝素联合应用对小鼠Lewis肺癌生长和肺血栓栓塞症的影响[J]. 首都医科大学学报, 2006, 27(1): 38-42.

Zhang Yuhui;Wang Chen;Zhang Liming;Zai Zhenguo;Pang Baoshen. Effect of VEGF Antisense Oligonucleotides Combined with Low Molecular Weight Heparin on Tumor Growth and Pulmonary Thromboembolism in Mice Lewis Lung Cancer[J]. Journal of Capital Medical University, 2006, 27(1): 38-42.

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