吲哚美辛抑制结肠癌移植瘤生长和微血管形成的实验研究

Experimental study of the inhibitory effect of indomethacin on the growth and angiogenesis of human colon cancer xenografts

目的研究非甾体抗炎药吲哚美辛对人结肠癌HCT116移植瘤生长和微血管形成的影响。方法建立人结肠癌裸鼠皮下移植瘤模型。随机分组:治疗组喂服吲哚美辛(3 mg·kg-1·d-1),对照组给予相应体积溶剂(0.2%二甲亚砜-生理盐水溶液)。4周后处死动物,采用免疫组化法检测肿瘤微血管密度(MVD)及肿瘤组织中血管内皮生长因子(VEGF)的表达,鼠抗人CD34标记微血管。结果治疗组与对照组皮下移植瘤体积分别为(458.89±32.07)mm3和(828.21±31.59)mm3(P<0.05),治疗组肿瘤生长受到明显抑制;瘤组织中MVD分别为19.50±5.32和37.40±4.93(P<0.001),VEGF的表达强度分别为1.19±0.17和1.90±0.48(P<0.01),MVD与VEGF变化呈正相关(rs=0.714,P<0.05)。实验结束时未见明显毒性反应。结论吲哚美辛能通过抑制肿瘤微血管形成发挥抗瘤作用,其机制可能与抑制VEGF的表达有关。

Objective To evaluate the efficacy of nonsteroidal anti-inflammatory drug indomethacin on tumor growth and microvessel angiogenesis of human colon cancer xenografts in nude mice. Methods Human colorectal cancer HCT116 cells were inoculated subcutaneously into BALB/c-nu/nu mice. After daily treatment with oral indomethacin for 4 weeks (3 mg·kg-1·d-1), the mice were sacrificed by cervical dislocation, and immunohistochemical staining was employed to determine microvessel density (MVD) and expression of vascular endothelial growth factors (VEGF) in the tumor tissues. Results Growth of HCT116 tumor was significantly suppressed by indomethacin. The tumor volume (mm3) was 458.89±32.07 in the treated group versus 828.21±31.59 in the control group (P<0.05). The MVDs of the treated and control groups were 19.50±5.32 and 37.40±4.93 respectively (P<0.001), and VEGF expressions were 1.19±0.17 and 1.90±0.48 (P<0.01), respectively. MVD and VEGF expression in the treated tumor tissue declined noticeably as compared with the controls. There was a positive correlation between the decrease of VEGF expression and that of MVD (rs=0.714, P<0.05). No obvious toxicity was observed in nude mice. Conclusion Indomethacin can inhibit the growth of transplanted human colorectal HCT116 tumor in association with a significant reduction in angiogenesis, which may be achieved through inhibition of VEGF.