INHIBITION OF TUMOR-GROWTH AND METASTASIS BY ANGIOGENESIS INHIBITOR TNP-470 ON BREAST-CANCER CELL-LINES IN-VITRO AND IN-VIVO

Antitumor and antimetastatic activity of the angiogenesis inhibitor O- (chloroacetyl-carbamoyl) fumagillol (TNP-470), a semisynthetic analogu e of fumagillin, was evaluated in breast cancer cell lines. In an in v itro MTT assay, after 72 hrs continuous exposure to TNP-470, growth in hibition was observed in all seven cell lines of murine (JYG-A, JYG-B, DD-762, and BALB/c-MC) or human (KPL-1, MDA-ME-231, and MKL-F) ori gi n, in which the 50% inhibitory concentrations (IC50) at 72 hrs treatme nt were 4.6, 4.4, 4.6, 10.1, 35.0, 25.3, and 33.4 mu g/ml, respectivel y. In an in vivo assay using JYG-A, JYG-B, KPL-1, and MDA-MB-231 cells by orthotopic (right thoracic mammary fat pad) transplantation in fem ale nude mice, TNP-470 at 30 or 50 mg/kg body weight was injected s.c. every other day from the day of tumor cell inoculation until the end of the experiment. The inhibitory effect on primary tumor growth was o btained in all four cell lines in a dose-dependent manner. In the 50 m g/kg TNP-470-treated group, the reductions in tumor weight of the JYG- A, JYG-B, KPL-1, and MDA-MB-231 cells with respect to the controls wer e 50%, 30%, 4%, and 49%, respectively. Metastasis was seen in the JYG- A, JYG-B, and KPL-1 cells. The numbers of mice bearing pulmonary metas tases of JYG-A and JYG-B cells and regional axillary lymph node metast ases of KPL-1. cells were reduced, and TNP-470 at the 50 mg/kg dose to KPL-1 cells significantly reduced lymph node metastases compared with the control. Although the weight gain was retarded in the TNP-470-tre ated mice, weight loss was not seen. TNP-470 was highly effective in t he treatment of breast cancer cells. These results suggest that the cl inical use of TNP-470 may be a promising treatment for breast cancer p atients.