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) fu magillol (TNP-470), an angiogenesis inhibitor, and cisplatin (CDDP), an ant i-neoplastic agent, were investigated using our established liver-metastasi zing pancreatic carcinoma line, HPC-3H4. HPC-3H4 was injected into the sple ens 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 receivi ng 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 gro up, liver metastasis developed in 14 of 15 mice (93.3%). Liver metastasis d eveloped 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 T NP-470 in combination with 0.25 mg/kg CDDP, TNP-470 in combination with CDD P displayed a significant inhibitory effect on liver metastasis compared to the control. Although TNP-470 alone and CDDP alone had no effect on the tu mor growth in vivo, 90 mg/kg TNP-470 in combination with 0.25 md/kg CDDP ha d a significant effect. In vitro examinations demonstrated that the growth of HPC-3H4 cells was only mildly inhibited by TNP-470, but the production o f vascular endothelial growth factor (VEGF) by HPC-3H4 was clearly inhibite d by TNP-470. The inhibitory effect on the production of VEGF was not stron g with CDDP treatment. These results indicate that the angiogenesis inhibit or TNP-470 in combination with low-dose CDDP has inhibitory activity agains t liver metastasis of human pancreatic carcinoma.