Inhibitory effect of the angiogenesis inhibitor TNP-470 on hepatocellular carcinomas

我们进行了以下研究来阐明血管生成抑制剂TNP-470对肝细胞癌生长的抑制作用。使用胆碱缺乏L-氨基酸限定（CDAA）饮食诱导大鼠肝细胞癌的研究。肝细胞癌通常在开始CDAA饮食后6至12个月开始开始发展。将大鼠分为4组：A组：7月龄至1岁注射TNP-470，B组：7月龄至1岁注射生理盐水，C组：1岁起注射TNP-470 4个月，D组：7月龄至1岁注射生理盐水。D组为1岁起注射生理盐水4个月组。1）4组间瘤前病变的发生率和大小无明显差异。TNP-470治疗组大鼠体重明显下降，但对肝硬化组织学及肝功能无明显影响。A组和C组肝癌细胞凋亡率高于B组和D组，A组和C组肝癌组织中血管密度较B组和D组有减少趋势.体外研究肝癌细胞与人内皮细胞共同培养后，其增殖速度明显快于无肝癌细胞的内皮细胞。虽然TNP-470的加入抑制了人内皮细胞的增殖，但对肝癌细胞没有抑制作用。这些发现表明抑制血管生成可能会抑制肝细胞癌的生长。

We performed the following studies to clarify the inhibitory effect of angiogenesis inhibitor, TNP-470 on the growth of hepatocellular carcinomas.1. Studies using hepatocellular carcinomas induced by a choline-deficient L-amino acid defined (CDAA) diet in rats. Hepatocellular carcinomas usually begin to develop from 6 to 12 months after the beginning of CDAA diet. Rats were classified into 4 groups : Group A,the rats which were injected with TNP-470 from 7 months to 1 year old ; Group B,the rats which were injected with saline from 7 months to 1 year old ; Group C,the rats which were injected with TNP-470 for 4 months from 1 year old ; Group D,the rats which were injected with saline for 4 months from 1 year old.1) The incidence and size of preneoplastic lesions were not different between four groups. While, the incidence and size of hepatocellular carcinoma in Group A significantly decreased in comparison with group B.Those in Group C also decreased in comparison with Group D.2) Although TNP-470 caused severe weight loss in treated rats, the histology of liver cirrhosis and liver function were not influenced.3) The preliferation of hepatocellular carcinoma was not different between four groups. The apoptotic ratio of hepatoma cells in Group A and Group C was higher than that in Group B and Group D.The vascularity in hepatocellular carcinoma in Group A and Group C tended to be decreased in comparison with that in Group B and Group D.2. in vitro studiesThe proliferation of human endothelial cells cultured with hepatoma cells was faster than those cells cultured without hepatoma cells. Although the proliferation of human endothelial cells was inhibited by the addition of TNP-470, hepatoma cells were not inhibited. These findings suggests that the inhibition of angiogenesis may suppress the growth of hepatocellular carcinoma.