INHIBITORY EFFECT OF THE ANGIOGENESIS INHIBITOR TNP-470 ON TUMOR-GROWTH AND METASTASIS IN NUDE-MICE BEARING HUMAN HEPATOCELLULAR-CARCINOMA

The antitumor and anti-metastatic effects of a potent angiogenesis inh ibitor, O-(chloroacetyl-carbamoyl)fumagillol (TNP-470), was investigat ed in a highly metastatic model of human hepatocellular carcinoma - LC I-D20. Small pieces of LCI-D20 tumor tissue were implanted subcutaneou sly into the right axillary region of 24 nude mice; the mice were then randomized into two groups. To one group, TNP-470 30 mg/kg was given as a subcutaneous injection every other day from day 1 to day 15 and t he mice were sacrificed on day 26. An antitumor effect of TNP-470 was clearly demonstrated by tumor weight (0.97 +/- 0.34 g compared to 2.04 +/- 0.34 g, P < 0.001) and alpha-Fetoprotein value (93 +/- 59 mu g/L compared to 769 +/- 282 mu g/L, P < 0.001). There was also an anti-met astatic effect of TNP-470. Lung metastases developed in only 1 of 12 m ice in the treated group, while they developed in 6 of mice of the con trol group. No severe side-effect of TNP-470 was found in this study. In vitro study revealed that the purified hepatoma cells were insensit ive to TNP-470 (the 50% inhibitory concentration was 43 mu g/ml). Thes e results suggest that the angiogenesis inhibitor TNP-470 has both str ong antitumor and anti-metastatic effects on a human hepatocellular ca rcinoma model in nude mice.