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 gr owth or metastasis has been reported, but the sustained antimetastatic effect of these agents has not been studied. We investigated the sust ained effect of TNP-470, an angiogenesis inhibitor, in rats with hepat ic metastasis following intraportal implantation of rat ascites hepato ma 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 o f 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 grou p (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 massiv e 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 TN P-470 at the lower dose, as evidenced by the absence of intraperitonea l 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 w ere observed in all rats at the end of treatment. These results sugges t that the sustained cytostatic effect of TNP-470 on vascular endothel ial cells may help to improve long-term survival by reducing the metas tatic burden. (C) 1996 Academic Press, Inc.