Matsuoka S
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
Hokkaido Igaku Zasshi. 1996 Jan;71(1):69-80.
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.
研究了新开发的血管生成抑制剂TNP - 470（AGM - 1470）单独使用以及与顺铂联合使用对荷瘤大鼠的影响。将Wistar - King A雄性大鼠皮下接种10⁷个经口服3'-甲基-4-二甲基氨基偶氮苯诱导产生的同基因培养肝癌细胞，以此作为荷瘤大鼠。给予TNP - 470后测量肿瘤大小和血清铜水平的变化。给予TNP - 470（5、10、20或30mg/kg，皮下注射，每日1次，共7天）以剂量依赖方式抑制肿瘤生长。同时给予TNP - 470（20mg/kg，皮下注射，每日1次，共7天）和顺铂（0.5mg/kg，皮下注射，每日1次，共7天）的大鼠，以及在给予TNP - 470（20mg/kg，皮下注射，每日1次，共7天）后给予顺铂（0.5mg/kg，皮下注射，每日1次，共7天）的大鼠，其抑制效果相同。这些抑制作用与单独给予顺铂（0.5mg/kg，皮下注射，每日1次，共7天）几乎相同。然而，在顺铂治疗（0.5mg/kg，皮下注射，每日1次）后给予TNP - 470（20mg/kg，皮下注射，每日1次，共7天），与这些组相比，显示出明显更高的抗肿瘤效果。给予TNP - 470可使正常大鼠和荷瘤大鼠的血清铜水平升高，且升高程度相同。正常大鼠停用TNP - 470后血清铜水平保持正常，而荷瘤大鼠在停用TNP - 470后的第一周血清铜水平下降，在停用2至3周后再次升高。血清铜水平的这种再次升高与停用TNP - 470后肿瘤的快速生长有关。此外，肿瘤中的血清铜水平与毛细血管密度之间也存在正相关。总之，TNP - 470对大鼠肝癌具有剂量依赖性的抗肿瘤作用，在顺铂之后给予时效果明显更高。停用TNP - 470治疗后的血清铜水平可能表明肿瘤组织中毛细血管的重新增殖。
