Inhibition of Liver Metastasis of Human Pancreatic Carcinoma by Angiogenesis Inhibitor TNP‐470 in Combination with Cisplatin

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.