Accumulated knwoledge regarding the important roles played by angiogenesis in solid
tumor growth and
metastasis has prompted the development of
angiogenesis inhibitors for clinical use in
cancer therapy. Among these inhibitors, O-(chloroacetyl-carbamoyl)
fumagillol (TNP-470) has been reported to have both antitumor and antimetastatic activities in rodent and human
tumor models. We recently established a new
metastasis model of MKL-4 human
breast cancer cells in female nude mice. This cell line is a co-transfectant of the MCF-7 cell line with genes of a potent
angiogenic factor,
fibroblast growth factor 4, and a
genetic marker, bacterial lac ¤ In this paper, we describe the inhibitory effects of
TNP-470 on
tumor angiogenesis, growth and
metastasis in this MKL-4
metastasis model.
Subcutaneous injection of 10 or 50 mg/kg of
TNP-470 every other day for two weeks obviously inhibited the
tumor growth and
metastasis of MKL-4 cells in female nude mice. The treatment of
TNP-470 at both doses significantly reduced the
tumor volumes, respectively, to 28% and 14% of that in the control group(p<0.05 in each comparison). The positive rate of
metastasis into the axillary lymph nodes was 100% in the control group, whereas it was only 33% in both of the treatment groups. Distant
metastasis into the inguinal lymph nodes, lungs, kidneys and liver also tended to decrease in both of the treatment groups. Immunohistochemical analysis using anti-
factor VIII antibody revealed that the number of microvessels in both of the treatment groups was significantly less than that in the control group(p<0.01 in each comparison). To the best of our knowledge, this is the first report describing simultaneous demonstration of the antiangiogenic, antitumor and antimetastatic effects of
TNP-470 on human
breast cancer cells in nude mice.