血管生成抑制剂内皮抑素对裸鼠人结肠癌异种移植瘤生长和转移的抑制作用

[Inhibition of growth and metastases of human colon cancer xenograft in nude mice by angiogenesis inhibitor endostatin].

作者信息

Zhang Guo-feng, Wang Yuan-he, Zhang Ming-ao, Wang Qiang, Luo Yun-bao, Wang Deng-shan, Han Ce-ran

机构信息

Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P. R. China.

出版信息

Ai Zheng. 2002 Jan;21(1):50-3.

PMID:12500397

Abstract

BACKGROUND & OBJECTIVE: Tumor angiogenesis is essential for growth and metastases of colon cancer. Angiogenesis inhibitors can induce apoptosis in colon cancer by inhibiting tumor angiogenesis and has strong inhibitory effect both on tumor growth and metastases of human colon cancer. Anti-angiogenic cancer therapy is important for selecting the timing and method of operation and program of complex treatment and enhancing the five-year survival rate of patients with colon cancer. In this study, we aimed to investigate the effects of angiogenesis inhibitor endostatin on the growth and metastases of colon cancer in vivo.

METHODS

Metastatic model simulating human colon cancer was established by orthotopic implantation of histologically intact human tumor tissue into colon wall of nude mice. Endostatin was administered s.c. at dose of 0 mg/kg, 5 mg/kg, 10 mg/kg and 20 mg/kg, every day for six weeks. Seven weeks after implantation, the tumor weight and inhibition rates and intratumoral microvessel density (MVD) and apoptotic index (AI) and the presence of metastases are evaluated respectively after the mice were sacrificed.

RESULTS

In compared with the untreated controls, growth of the orthotopically implanted tumor was significantly reduced in weight in mice treated with endostatin with an inhibition rate of 0%, 67.9%, 84.0%, and 90.1% at the dosage of 0 mg/kg, 5 mg/kg, 10 mg/kg, and 20 mg/kg, respectively. The MVD also decreased significantly in the treated mice [(12.8 +/- 4.1) versus (5.9 +/- 2.5), (2.2 +/- 1.4) and (0.74 +/- 0.3)]. The AI increased significantly in the treated mice [(3.87 +/- 2.61)%, versus (6.89 +/- 5.18%), (13.24 +/- 4.76)% and (20.97 +/- 9.04)%]. The incidences of peritoneal metastases were also significantly inhibited in the treated mice (90.0% versus 36.4%, 25.0%, and 0%). The incidences of liver metastases were also significantly inhibited in the treated mice (80.0% versus 27.3%, 16.7% and 0%). Tumor metastases to the liver and peritoneaum were also significantly inhibited in a dose-dependent manner (P < 0.05).

CONCLUSIONS

Angiogenesis inhibitor endostatin can induce apoptosis in colon cancer by inhibiting tumor angiogenesis and has strong inhibitory effect both on tumor growth and metastases of human colon cancer xenograft in nude mice.

摘要

背景与目的

肿瘤血管生成对结肠癌的生长和转移至关重要。血管生成抑制剂可通过抑制肿瘤血管生成诱导结肠癌细胞凋亡，对人结肠癌的肿瘤生长和转移均有较强的抑制作用。抗血管生成癌症治疗对于选择手术时机和方法、综合治疗方案以及提高结肠癌患者的五年生存率具有重要意义。本研究旨在探讨血管生成抑制剂内皮抑素对体内结肠癌生长和转移的影响。

方法

通过将组织学完整的人肿瘤组织原位植入裸鼠结肠壁建立模拟人结肠癌的转移模型。内皮抑素按0 mg/kg、5 mg/kg、10 mg/kg和20 mg/kg的剂量皮下注射，每日一次，共六周。植入后七周，处死小鼠后分别评估肿瘤重量、抑制率、瘤内微血管密度（MVD）、凋亡指数（AI）及转移情况。

结果

与未治疗的对照组相比，内皮抑素治疗的小鼠原位植入肿瘤的生长重量显著降低，0 mg/kg、5 mg/kg、10 mg/kg和20 mg/kg剂量组的抑制率分别为0%、67.9%、84.0%和90.1%。治疗组小鼠的MVD也显著降低[（12.8±4.1）对（5.9±2.5）、（2.2±1.4）和（0.74±0.3）]。治疗组小鼠的AI显著升高[（3.87±2.61）%对（6.89±5.18）%、（13.24±4.76）%和（20.97±9.04）%]。治疗组小鼠的腹膜转移发生率也显著降低（90.0%对36.4%、25.0%和0%）。治疗组小鼠的肝转移发生率也显著降低（80.0%对27.3%、16.7%和0%）。肿瘤向肝脏和腹膜的转移也呈剂量依赖性显著降低（P<0.05）。