Inhibition of Tumor Growth and Metastasis of Rodent Tumors by the Angiogenesis Inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470; AGM-1470)

The effect of the potent angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470), a semisynthetic analogue of fumagillin, on tumor growth and metastasis was studied using rodent tumors. Injection of TNP-470 s.c. inhibited tumor growth in a dose-dependent manner, and the tumor sizes of B16BL6 melanoma, M5076 reticulum cell sarcoma, Lewis lung carcinoma, and Walker 256 carcinoma were maximally reduced to 16, 10, 17, and 4% of that in the respective control. The activity of TNP-470 upon i.v. injection was slightly weaker than that following s.c. injection. This tendency was observed for all the tumors tested. Injection i.v. (infusion) of TNP-470 increased the life span of Walker 256 carcinoma-bearing rats by 183% over the control, while bolus i.v. injection increased the life span by only 47%. TNP-470 reduced the number of pulmonary metastatic foci of i.v. inoculated B16BL6 melanoma in a dose-dependent manner, and the number of metastatic foci was reduced to 10% of that in the control by treatment with TNP-470 at 60 mg/kg, 3 times/week. The mean survival time of B16BL6 tumor-bearing mice treated with TNP-470 using this regimen was extended by 56% over that of control mice. TNP-470 at 10 mg/kg every day also reduced the number of metastatic foci of M5076 sarcoma in the liver after resection of the tumor from the primary site. Adriamycin at the same dose only slightly reduced the number of metastatic foci, even though TNP-470 and Adriamycin showed roughly equal inhibitory activity against M5076 sarcoma growth. TNP-470 extended the mean survival time of M5076 tumor-bearing mice by more than 100% over that of control mice at 30 mg/kg every 3 days, while Adriamycin extended mean survival times by maximally 20% at 10 mg/kg. These results show that the angiogenesis inhibitor TNP-470 has strong inhibitory activities against in vivo growth and metastasis of a wide variety of tumors.