Shishido T, Yasoshima T, Denno R, Mukaiya M, Sato N, Hirata K
First Department of Surgery, Sapporo Medical University School of Medicine.
Jpn J Cancer Res. 1998 Sep;89(9):963-9. doi: 10.1111/j.1349-7006.1998.tb00655.x.
The anti-tumor and anti-metastatic effects of O-(chloroacetyl-carbamoyl) fumagillol (TNP-470), an angiogenesis inhibitor, and cisplatin (CDDP), an anti-neoplastic agent, were investigated using our established liver-metastasizing pancreatic carcinoma line, HPC-3H4. HPC-3H4 was injected into the spleens of nude mice. Mice were randomly divided into 5 groups; a control group given saline solution, a group receiving 45 mg/kg TNP-470, a group receiving 90 mg/kg TNP-470, a group receiving 90 mg/kg TNP-470 in combination with 0.25 mg/kg CDDP, and a group receiving 0.25 mg/kg CDDP. In the control group, liver metastasis developed in 14 of 15 mice (93.3%). Liver metastasis developed in 9 of 11 mice (81.8%) receiving 0.25 mg/kg CDDP. It developed in 11 of 15 mice (73.3%) receiving 45 mg/kg TNP-470, in 17 of 18 mice (94.4%) receiving 90 mg/kg TNP-470, and in 4 of 10 mice (40%) receiving 90 mg/kg TNP-470 in combination with 0.25 mg/kg CDDP. TNP-470 in combination with CDDP displayed a significant inhibitory effect on liver metastasis compared to the control. Although TNP-470 alone and CDDP alone had no effect on the tumor growth in vivo, 90 mg/kg TNP-470 in combination with 0.25 mg/kg CDDP had a significant effect. In vitro examinations demonstrated that the growth of HPC-3H4 cells was only mildly inhibited by TNP-470, but the production of vascular endothelial growth factor (VEGF) by HPC-3H4 was clearly inhibited by TNP-470. The inhibitory effect on the production of VEGF was not strong with CDDP treatment. These results indicate that the angiogenesis inhibitor TNP-470 in combination with low-dose CDDP has inhibitory activity against liver metastasis of human pancreatic carcinoma.
使用我们建立的肝转移胰腺癌模型HPC-3H4，研究了血管生成抑制剂O-(氯乙酰-氨甲酰)烟曲霉素(TNP-470)和抗肿瘤药物顺铂(CDDP)的抗肿瘤及抗转移作用。将HPC-3H4注入裸鼠脾脏。小鼠被随机分为5组；一组给予生理盐水作为对照组，一组接受45mg/kg的TNP-470，一组接受90mg/kg的TNP-470，一组接受90mg/kg的TNP-470与0.25mg/kg的CDDP联合用药，一组接受0.25mg/kg的CDDP。对照组中，15只小鼠中有14只(93.3%)发生肝转移。接受0.25mg/kg CDDP的11只小鼠中有9只(81.8%)发生肝转移。接受45mg/kg TNP-470的15只小鼠中有11只(73.3%)发生肝转移，接受90mg/kg TNP-470的18只小鼠中有17只(94.4%)发生肝转移，接受90mg/kg TNP-470与0.25mg/kg CDDP联合用药的10只小鼠中有4只(40%)发生肝转移。与对照组相比，TNP-470与CDDP联合用药对肝转移显示出显著的抑制作用。虽然单独使用TNP-470和单独使用CDDP对体内肿瘤生长没有影响，但90mg/kg的TNP-470与0.25mg/kg的CDDP联合用药有显著效果。体外实验表明，TNP-470对HPC-3H4细胞的生长仅有轻微抑制作用，但TNP-470能明显抑制HPC-3H4细胞产生血管内皮生长因子(VEGF)。CDDP治疗对VEGF产生的抑制作用不强。这些结果表明，血管生成抑制剂TNP-470与低剂量CDDP联合使用对人胰腺癌肝转移具有抑制活性。
