SU5416抑制胃癌生长和肝转移的实验研究

Inhibition of growth and metastasis of implanted human gastric cancer in nude mice by SU5416

目的 研究血管内皮细胞生长因子抑制物SU5 4 16对裸鼠原位种植人胃癌生长和肝转移抑制作用 ,探讨其对癌细胞凋亡的影响。方法 建立人胃癌裸鼠原位种植转移模型 ,随机分为 4组。种植后第 1周开始 ,分别自腹腔注射生理盐水 (对照组 )、5 氟尿嘧啶 (30mg·kg-1·d-1,5 FU组 )、SU5 4 16(15mg·kg-1·d-1,SU5 4 16组 )、5 FU与SU5 4 16联合应用 (5 FU 30mg·kg-1·d-1,SU5 4 16 15mg·kg-1·d-1,5 FU +SU5 4 16组 ) ,每天 1次 ,共 7周。第 8周处死动物 ,测量原位肿瘤瘤重、抑瘤率、微血管密度(MVD)、胃癌细胞凋亡指数 (AI) ,观察肿瘤细胞肝转移情况。结果 对照组、5 FU组、SU5 4 16组、5 FU+SU5 4 16组的原位肿瘤瘤重分别为 (1.35± 0 .4 2 )、(0 .75± 0 .33)、(0 .34± 0 .14 )及 (0 .2 1± 0 .15 ) g ;抑瘤率分别为 4 4 .5 % ,79.3% ,84 .4 % ;肝转移率分别为 90 .0 % ,36 .4 % ,2 5 .0 % ,0 %。MVD分别为 14 .6± 5 .8,13.1± 4 .7,3.9± 1.8,2 .1± 1.5 ;AI分别为 (3.76± 2 .2 5 ) % ,(6 .81± 4 .92 ) % ,(9.82± 3.76 ) % ,(17.6 5± 9.85 ) %。与对照组、5 FU组相比 ,SU5 4 16组、5 FU +SU5 4 16组胃癌生长、肝转移及MVD受到明显抑制 (P <0 .0 5 ) ,AI明显增高 (P <0 .0 5 )。

Objective To study the effects of angiogenesis inhibitor SU5416 on the growth and metastasis to the liver of gastric cancer and to investigate its effect on the apoptosis of gastric cancer cells. Methods Metastatic model simulating human gastric cancer was established by orthotopic implantation of histologically intact human tumor tissue into gastric wall of nude mice. Mice were randomly divided into 4 groups: control group (saline solution), 5 FU group (fluorouracil 30 mg·kg -1 ·d -1 i.p.), SU5416 group (SU5416 15 mg·kg -1 ·d -1 i.p.), and combined treatment of both 5 FU and SU5416 group. Eight weeks after implantation, the tumor weight, inhibition rates, intratumoral microvessel density (MVD), apoptotic index (AI), and the presence of metastasis were evaluated respectively after the mice were sacrificed. Results Compared with the control group, the growth of the orthotopically implanted tumor was significantly inhibited due to the reduced weight and the inhibition rate of tumor was 44.5%, 79.3%, and 84.4% respectively in mice treated with 5 FU, SU5416 and both. The incidences of liver metastases were also significantly decreased in the 5 FU group, SU5416 group, and combined group compared with those in control group (36.4%, 25.0%, and 0% vs 90.0%). The MVD was decreased significantly in the treated mice ( 14.6 ± 5.8 vs 13.1±4.7, 3.9± 1.8 , and 2.1±1.5). The AI was increased significantly in the treated mice [(3.76±2.25)% vs (6.81± 4.92 )%, (9.82±3.76)% and (17.65±9.85)%]. The growth and liver metastasis of human gastric cancer implanted in nude mice were more significantly inhibited in the SU5416 group and combined group than in control group and 5 FU group ( P <0.05).Conclusions SU5416 can induce apoptosis in gastric cancer by inhibiting tumor angiogenesis and has a strong inhibitory effect both on tumor growth and on metastasis of to live gastric cancer implanted in nude mice. Combination of SU5416 with cytotoxic agents could be more effective.