[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.
Matsuoka
S
S
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D003300:Copper / Q000097:blood*; D003510:Cyclohexanes; D003864:Depression, Chemical; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009389:Neovascularization, Pathologic; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D003300:Copper; D002945:Cisplatin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol