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

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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.