阳秋香等

[摘要] 目的 探讨贝伐单抗联合放疗对人肺癌A549细胞株裸鼠移植瘤的作用。 方法 将人肺癌A549细胞接种于24只裸鼠后腿皮下，10 d后肿瘤体积在100～200 mm3之间，按随机数字表法分为对照组（无菌生理盐水注射）、贝伐单抗组（每次注射贝伐单抗10 mg/kg，每周1次，共3次）、放疗组（5 Gy/次，共2次）、贝伐单抗联合放疗组（联用贝伐单抗和放疗）。治疗过程中测量肿瘤大小及重量，41 d后处死裸鼠，切取移植瘤组织。采用免疫组织化学方法检测各组标本的肿瘤微血管密度（MVD）和血管内皮生长因子（VEGF）的表达情况，并进行统计学分析。 结果 贝伐单抗联合放疗组移植瘤瘤体生长与对照组比较明显受抑制（P < 0.05），抑瘤率达82.8%；免疫组织化学显示贝伐单抗联合放疗组MVD、VEGF表达[（7.37±4.11）、（3.10±0.98）]较对照组[（14.40±5.01）、（6.00±1.90）]明显减少，差异有统计学意义（P < 0.05）。 结论 贝伐单抗联合放疗可能通过抑制VEGF表达而增强非小细胞肺癌的放射敏感性。

[关键词] 贝伐单抗；放疗；移植瘤；肺癌

[中图分类号] R734.2 [文献标识码] A [文章编号] 1673-7210（2015）05（b）-0018-04

Effect of Bevacizumab combined with radiotherapy on lung cancer xenografts in nude mice

YANG Qiuxiang ZHANG Huanhuan YUAN Taize LIANG Ying YU Jinxiu WANG Wenjin ZHANG Xiuping

Department of Radiotherapy， the Affiliated Cancer Hospital of Guangzhou Medical University， Guangdong Provicne， Guangzhou 510095， China

[Abstract] Objective To explore the effect of Bevacizumab combined with radiotherapy on lung cancer xenografts in nude mice. Methods The human lung cancer A549 cells were injected sc into the hind legs of nude mice. When the volume of tumor was about 100-200 mm3 after 10 days， nude mice were randomly divided into four groups： control group （injected with saline solution）， Bevacizumab group （treated with Bevacizumab 10 mg/kg， once a week， for three times）， radiotherapy group （5 Gy/fraction， twice） and Bevacizumab in combination with radiotherapy group （treated with Bevacizumab and radiotherapy）. The tumor size and weight were measured during the treatment. The mice were sacrificed after 41 days. The tumor tissues were collected. The expression of microvessel density （MVD） and vascular endothelial growth factor （VEGF） were detected in histologic sections of xenografts by immunohistochemistry and analyzed by statistical method. Results The subcutaneous xenografts in Bevacizumab in combination with radiotherapy group were decreased significantly as compared with control group （P < 0.05）. The tumor inhibition rate was 82.8%. Immunohistochemistry revealed that Bevacizumab in combination with radiotherapy group could remarkably reduce the MVD and the expression of VEGF [（7.37±4.11）， （3.10±0.98）] as compared with the control group [（14.40±5.01）， （6.00±1.90）] （P < 0.05）. Conclusion Bevacizumab enhances the radiosensitivity of non-small cell lung cancer by the inhibition of VEGF expression.

[Key words] Bevacizumab； Radiotherapy； Xenograft； Lung cancer

肺癌是目前世界上发病率和病死率最高的恶性肿瘤。非小细胞肺癌（non-small cell lung cancer，NSCLC）占肺癌总数的80%～85%，大多数患者就诊时已处于晚期，主要采用放、化疗及靶向治疗等综合治疗，因肿瘤巨大和/或放射抗拒等原因，疗效往往不理想，5年总生存率约为17%[1]。因而通过将放疗与靶向治疗联合来改善放疗抵抗、提高放疗疗效成为目前研究的热点。贝伐单抗（Bevacizumab）是一种以血管内皮生长因子（vascular edothelial growth factor，VEGF）为靶点的分子靶向药物，已经被美国食品与药物管理局（FDA）批准用于治疗转移性结直肠癌、转移性非小细胞肺癌、转移性肾癌等恶性肿瘤[2]。研究表明贝伐单抗具有放射治疗增敏的作用[3]。于丹丹等[4]将贝伐单抗与放疗联合并观察其对乳腺癌移植瘤生长的影响，发现联合治疗组对肿瘤生长的抑制作用最为显著，并进一步发现联合治疗组缺氧诱导因子1α（HIF-1α）、VEGF水平明显降低，提示贝伐单抗可能通过抑制肿瘤细胞增殖和减少血管生成，从而抑制肿瘤生长。……