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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。
Objective To investigate the effects of combined use of vascular endothelial growth factor (VEGF) antisense oligonucleotide (ASODN) and low molecular weight heparin (LMWH) on the growth, coagulation and pulmonary thromboembolism (Lewis pulmonary carcinoma) in Lewis lung carcinoma in mice and its mechanism. Methods Forty Lewis lung cancer model mice were randomly divided into control group, VEGF-ASODN group, VEGF missense oligonucleotide (MSODN) group, LMWH group and combination therapy group, with 8 rats in each group. VEGF-ASODN, VEGF-MSODN, LMWH (Fahrenheit) and VEGF-ASODN + Ampelophenia were injected subcutaneously every other day for 15 times. Detection of subcutaneous xenograft changes. Tumor tissue microvessel density (MVD) was detected by immunohistochemistry. The plasma concentrations of VEGF and coagulation activator tissue factor (TF) were measured by enzyme-linked immunosorbent assay. Tissue tissue, heart, lung, brain, kidney, liver and other tissues and organs of thrombosis and embolism were examined by HE staining. The expression of VEGF and TF protein in tumor tissue was detected by Western blot. Results The antitumor rates of ASODN, LMWH and combination therapy group were 47.34%, 27.31% and 59.03%, respectively. The tumor inhibition rates and MVD in these three groups were significantly different from those in control group and MSODN group (P <0.05 ). The plasma concentrations of VEGF in the ASODN group and the combination group were significantly lower than those in the control group (9.66 ± 1.02 ng / L, 9.39 ± 2.26 ng / L, respectively, P <0.05 ). The plasma TF concentrations of LMWH group and combination group were (20.00 ± 1.26) ng / L and (23.50 ± 5.62) ng / L, respectively, which were significantly lower than those of the control group (27.08 ± 5.40 ng / L) 0.05). The incidences of PTE in control group, ASODN group, MSODN group, LMWH group and combination therapy group were 37.5%, 50.0%, 37.5%, 25.0% and 25.0%, respectively. The expression of VEGF protein in ASODN group was weak Strong. Conclusions The combination of VEGF-ASODN and LMWH has a synergistic antitumor effect. However, VEGF-ASODN has a procoagulant effect, which increases the risk of PTE, whereas LMWH decreases the tendency of hypercoagulability.