Endostatin对结肠癌生长和转移抑制作用的实验研究

背景与目的:结肠癌的生长、转移是血管生成依赖性的,血管生成抑制剂有望通过抑制肿瘤血管生成,诱导结肠癌细胞凋亡,有效地抑制结直肠癌的生长和转移。肿瘤的抗血管生成治疗对选择手术时机和方式、制定综合治疗方案,提高结肠癌患者5年生存率都具有重要意义。本实验研究血管生成抑制因子Endostatin对结肠癌生长和转移的抑制作用,并探讨其对结肠癌细胞凋亡的影响。方法:采用人结肠腺癌细胞株SW1116完整组织块裸鼠原位种植,建立类似于临床的结肠癌转移裸鼠模型。种植后第1周开始皮下注射Endostatin,每天一次,剂量为0mg/kg(对照组)、5mg/kg、10mg/kg、20mg/kg(治疗组),共用6周。种植后第7周处死动物,测量原位肿瘤瘤重、抑瘤率、肿瘤微血管密度(intratumoralmicrovesseldensity,MVD)、肿瘤细胞凋亡指数(apoptoticindex,AI),观察肿瘤细胞腹膜、肝、其他脏器转移及腹水情况。结果:Endostatin剂量为0mg/kg、5mg/kg、10mg/kg、20mg/kg时,原位肿瘤瘤重分别为(1.31±0.36)g、(0.42±0.17)g、(0.21±0.09)g、(0.13±0.05)g;抑瘤率分别为0%、67.9%、84.0%、90.1%;MVD分别为(12.8±4.1)、(5.9±2.5)、(2.2±1.4)、(0.74±O.3);AI分别为(3.87±2.61)%、(6.89±5.18)%、(13.24±4.76)%、(20.97±9.04)%;腹膜转移率分别为9

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

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.