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 analogue offumagillin, was evaluated in breast cancer cell lines. In an in vitro MTTassay, after 72 hrs continuous exposure to TNP-470, growth inhibition wasobserved in all seven cell lines of murine (JYG-A, JYG-B, DD-762, andBALB/c-MC) or human (KPL-1, MDA-MB-231, and MKL-F) origin, in which the50% inhibitory concentrations (IC₅₀) at 72 hrstreatment were 4.6, 4.4, 4.6, 10.1, 35.0, 25.3, and 33.4 µg/ml,respectively. In an in vivo assay using JYG-A, JYG-B, KPL-1, and MDA-MB-231cells by orthotopic (right thoracic mammary fat pad) transplantation infemale 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 theexperiment. The inhibitory effect on primary tumor growth was obtained inall four cell lines in a dose-dependent manner. In the 50 mg/kgTNP-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 were 50%,30%, 4%, and 49%, respectively. Metastasis was seen inthe JYG-A, JYG-B, and KPL-1 cells. The numbers of mice bearing pulmonarymetastases of JYG-A and JYG-B cells and regional axillary lymph nodemetastases of KPL-1 cells were reduced, and TNP-470 at the 50 mg/kg dose toKPL-1 cells significantly reduced lymph node metastases compared with thecontrol. Although the weight gain was retarded in the TNP-470-treated mice,weight loss was not seen. TNP-470 was highly effective in the treatment ofbreast cancer cells. These results suggest that the clinical use of TNP-470may be a promising treatment for breast cancer patients.