The angiogenesis inhibitor TNP-470 (AGM-1470) improves long-term survival of rats with liver metastasis.

An excellent therapeutic effect of angiogenesis inhibitors on tumor growth or metastasis has been reported, but the sustained antimetastatic effect of these agents has not been studied. We investigated the sustained effect of TNP-470, an angiogenesis inhibitor, in rats with hepatic metastasis following intraportal implantation of rat ascites hepatoma AH-130 cells. TNP-470 was administered subcutaneously at 15 mg/kg (L-TNP) or 30 mg/kg (H-TNP) on alternate days for 2 weeks. The number of liver metastases was significantly reduced in both the L-TNP (85.1 +/- 77.6) and H-TNP (31.7 +/- 49.6) groups compared to the control group (300.7 +/- 100.7) (P < 0.01) at 14 days after the start of treatment. Although all rats in the control group died within 1 month of massive liver metastasis, the L-TNP and H-TNP, respectively, had a survival rate of 82 and 60%, at 4 months (P < 0.001). Absence of toxicity of TNP-470 at the lower dose, as evidenced by the absence of intraperitoneal or intrapleural bleeding, contributed to a better prognosis in the L-TNP group. Interestingly, a small dormant metastatic focus was found in only 1 of 15 rats surviving for 4 months, whereas metastatic foci were observed in all rats at the end of treatment. These results suggest that the sustained cytostatic effect of TNP-470 on vascular endothelial cells may help to improve long-term survival by reducing the metastatic burden.