目的：探讨以DNA损伤修复基因脱嘌呤/脱嘧啶核酸内切酶基因（apurinic/aprimidinic endonuclease1，APE1）为靶点的siRNA在骨肉瘤治疗中的作用及其与贝伐单抗（bevacizumab，Avastin）的协同效应。方法：建立人骨肉瘤9901细胞荷瘤裸鼠模型，16只荷瘤鼠随机分为4组：EGFP对照组，APE1 siRNA治疗组，Avastin治疗组和联合治疗组（Avastin+APE1 siRNA）。观察移植瘤生长情况并计算抑瘤率，免疫组织化学法检测肿瘤组织微血管密度和Ki67表达，TUNEL法检测肿瘤细胞凋亡，激光共聚焦检测肿瘤组织的缺氧状态，Western blotting检测肿瘤组织内VEGF蛋白的表达。结果：与APE1 siRNA治疗组和Avastin治疗组相比，Avastin+APE1 siRNA治疗组的抑瘤率显著增加（P<0.01）。各治疗组的微血管密度及Ki67表达明显低于对照组，且Avastin+APE1 siRNA治疗组微血管密度和Ki67表达显著低于单独治疗组（P<0.01）。各治疗组的凋亡指数明显高于对照组，且Avastin+APE1 siRNA治疗组明显高于单独治疗组（P<0.01）。APE1siRNA或Avastin治疗均可引起肿瘤组织缺氧，抑制肿瘤组织中VEGF的表达，Avastin+APE1 siRNA治疗效果更加明显。结论：以APE1为靶点的siRNA能显著抑制裸鼠移植骨肉瘤的血管生成和瘤体生长，并诱导肿瘤细胞凋亡，且与Avastin具有协同作用。

Objective:To investigate the effect of APE1targeting siRNA (APE1 siRNA) on implanted osteosarcoma and its synergetic role with bevacizumab (vascular endothelial growth factor antibody, Avastin). Methods: Human osteosarcoma 9901 cellbearing nude mouse model was established. Sixteen tumorbearing mice were randomly divided into 4 groups: EGFP control group, APE1 siRNA group, Avastin group and combined treatment group (Avastin+APE1 siRNA). The growth of implanted tumors was measured during treatment, and tumor inhibitotry rate was calculated. Meanwhile, microvessel density (MVD) and Ki67 expression in tumor tissues were examined by immunohistochemistry. Apoptosis of tumor cells was examined by TUNEL. Hypoxia status of tumor tissues was determined by laser cofocal scanning microscopy. Expression of VEGF protein in tumor tissues was detected by Western blotting. Results: The tumor inhibitory rate of Avastin+APE1 siRNA group was significantly increased compared with those of APE1 siRNA group and Avastin group (P<0.01). The MVD and Ki67 expressions in therapy groups were significantly lower than those in control group; moreover, the MVD and Ki67 expressions in Avastin+APE1 siRNA group were remarkedly lower than those in APE1 siRNA group or Avastin group (P<0.01). The apoptosis index (AI) in therapy groups was significantly higher than that in control group, with AI in Avastin+APE1 siRNA group being markedly higher than those in the other two groups (P<0.01). Hypoxia status in tumor tissues was enhanced and VEGF expression was inhibited in APE1 siRNA group or Avastin group; furthermore, hypoxia status and VEGF expression in Avastin+APE1 siRNA group were greatly changed.Conclusion: APE1targeting siRNA can inhibit the angiogenesis and growth of implanted osterosarcoma, and induce apoptosis of tumor cells, which shows a synergistic role with Avastin in the treatment of osteosarcoma.

国家自然科学基金资助项目（No. 30801368）