贝伐单抗抑制骨肉瘤血管生成及与放疗的协同作用研究

Studies on the inhibitory effect of bevacizumab on angiogenesis in osteosarcoma and the synergetic effcet of bevacizumab with radiotherapy in nude mice

目的观察贝伐单抗及其联合放疗对骨肉瘤裸鼠移植瘤血管生成的抑制作用。方法人骨肉瘤细胞系9901接种的裸鼠16只,随机均分为4组。贝伐单抗组(每周注射贝伐单抗2mg/kg,1次/周,共2次),放疗组(5Gy/周,共2次),联合组(联用贝伐单抗和放疗)和对照组(无菌生理盐水注射)。治疗过程中测量肿瘤长径、短径,并计算肿瘤体积,治疗第13天计算抑瘤率(TIR)。通过病理观察和免疫组织化学染色法观察肿瘤的坏死、微血管密度(MVD)以及肿瘤细胞的增殖和凋亡情况。结果贝伐单抗组、放疗组和联合组的TIR分别为32.87%、26.39%和87.50%(P<0.01),3组的肿瘤坏死率分别为11.49%±0.20%,10.30%±0.12%和27.15%±1.08%(P<0.01)。对照组的MVD及增殖指数高于、凋亡指数低于其余各组(P<0.01),联合组的MVD及增殖指数低于、凋亡指数高于放疗组和贝伐单抗组(P<0.01)。结论贝伐单抗能显著抑制骨肉瘤的血管生成和肿瘤细胞的增殖,诱导细胞凋亡,且贝伐单抗与放疗具有协同作用。

Objective To explore the inhibitory effect of bevacizumab, a kind of vascular endothelial growth factor antibody, and bevacizumab combined with radiotherapy on against angiogenesis in osteosareoma of nude mice. Methods Sixteen nude mice inoculated with human osteosarcoma cell line 9901 were randomly divided into four groups： bevacizumab group （only treated with bevaeizumab 2mg/ kg, once a week for two weeks）, radiotherapy group （5 Gy per week, twice）, combined treatment group （treated with bevacizumab and radiotherapy） and control group （injected with saline solution）. Long and short diameters of the tumors were measured and the volume was calculated during treatment. The tumor inhibition rate （TIR） was calculated on the day 13 after treatment. Meanwhile the mierovessel density （MVD）, necrosis, proliferation index （PI） and apoptotic index （AI） were observed pathologically by immunohistochemical staining. Results The TIRs were 32.87%, 26.39% and 87.50% （P〈0.01）, and the necrotic proportion was 11.49%±0.20%, 10.30%± 0. 12%and 27. 15%±1. 08% （P〈0. 01） in bevacizumab group, radiotherapy group and combination treatment group, respectively. The MVD and PI were significantly higher, while AI was remarkably lower in control group than in the other groups （P〈0. 01）, while the MVD and PI were significantly lower and PI was remarkably higher in combined treatment group than in both bevacizumab group and radiotherapy group （P〈0. 01）. Conclusions Bevacizumab may remarkably inhibit the osteosarcoma angiogenesis and tumor cell proliferation, induce apoptosis, and has a potential synergistic action with radiotherapy in antiangiogenesis.