Prevention of hepatic metastasis of human colon cancer by angiogenesis inhibitor TNP-470.

The antimetastatic effect of a potent angiogenesis inhibitor, O-(chloroacetyl-carbamoyl)fumagillol (TNP-470), was investigated in nude mice implanted with human colon cancer. Small pieces of tumors from three established human colon cancer cell lines (TK-3, TK-4, and TK-9), which were maintained in nude mice, were implanted into the cecal wall of nude mice via a small incision in the serosa. TNP-470 (20 or 30 mg/kg) was given s.c. every other day from day 10 after implantation, and the mice were sacrificed after 6 weeks. There was no difference in the weight of the implanted tumors (control group: 0.45 +/- 0.29 g versus treated group: 0.49 +/- 0.27 g). An antimetastatic effect of TNP-470 was clearly demonstrated in a dose-dependent manner. In the mice given 20 mg/kg TNP-470, liver metastasis developed in 3 of 10 cases. In the 30-mg/kg group, metastasis developed in only 1 of 17 mice, while it developed in 22 of 32 mice of the control group. The number of metastatic foci was significantly less in the treated groups. TNP-470 effectively prevented liver metastasis, however, but had no effect on the growth of the primary tumor. These results indicate that the angiogenesis inhibitor TNP-470 has a strong inhibitory activity against in vivo hepatic metastasis of human colon cancer.