[Anti-tumor effects of an angiogenesis inhibitor, TNP-470 (AGM-1470) alone and in combination with cisplatinum, and changes in serum copper levels in liver cancer bearing rats].

Effects of a newly developed angiogenesis inhibitor, TNP-470 (AGM-1470) alone and in combination with cisplatinum on tumor-bearing rats were investigated. Wistar-King A male rats were subcutaneously inoculated with 10(7) cultured syngeneic liver cancer cells that had been induced by oral intake of 3'-methyl-4-dimethylaminoazobenzen, and were used as tumor-bearing rats. Tumor sizes and changes in serum copper levels were measured after administration of TNP-470. Administration of TNP-470 (5, 10, 20 or 30mg/kg, s.c., daily for 7 days) inhibited tumor growth in a dose-dependent manner. The suppressive effects were the same in the rats which were administered TNP-470 (20mg/kg, s.c., daily for 7 days) and cisplatinum (0.5 mg/kg, s.c., daily for 7 days) simultaneously, and rats administered cisplatinum (0.5mg/kg, s.c., daily for 7 days) following TNP-470 (20mg/kg, s.c., daily for 7 days). These inhibitory effects were almost the same as that of cisplatinum (0.5mg/kg, s.c., daily for 7 days) alone. While, administration of TNP-470 (20mg/kg, s.c., daily for 7 days) following cisplatinum treatment (0.5 mg/kg, s.c., daily) showed markedly higher anti-tumor effects, compared with these groups. Administration of TNP-470 caused elevation of serum copper levels in normal rats as well as tumor-bearing rats with the same degree. Serum copper levels remained normal after discontinuation of TNP-470 in normal rats, while in tumor-bearing rats, it decreased during the first week and re-elevated in 2 to 3 weeks after discontinuation of TNP-470. This re-elevation of serum copper levels was related to rapid tumor growth after discontinuation of TNP-470. Furthermore, there was also a positive correlation between serum copper levels and capillary density in the tumor. In conclusion, TNP-470 had anti-tumor effect in a dose-dependent manner against a rat liver cancer, with markedly higher effects when it was administered following cisplatinum. Serum copper levels after discontinuation of TNP-470 treatment might indicate re-proliferation of the capillaries in the tumor tissue.