2-Methoxyestradiol (2-ME), an endogenous
estrogen metabolite which disrupts microtubule function, has been shown to inhibit proliferating cells in vitro and suppress certain murine
tumors in vivo. In vitro screening has determined that
breast cancer cell lines are most sensitive to inhibition by
2-ME. Additionally,
2-ME has been shown to inhibit angiogenesis in vitro. We tested whether
2-ME suppresses
cytokine-induced angiogenesis in vivo and inhibits growth of a human
breast carcinoma in severe combined immunodeficient mice. A model of
basic fibroblast growth factor (bFGF) and
vascular endothelial growth factor (
VEGF)-induced
corneal neovascularization in C57BL/6 mice was used to evaluate the antiangiogenic effects of
2-ME and other microtubule inhibitors such as
Taxol,
vincristine, and
colchicine.
2-ME (150 mg/kg p.o., n = 20) inhibited bFGF and
VEGF-induced neovascularization by 39% and 54%, respectively.
Taxol (6 mg/kg i.p., n = 17) inhibited bFGF and
VEGF-induced neovascularization by 45% and 37%, respectively.
Vincristine (0.2 mg/kg i.p., n = 8) and
colchicine (0.25 mg/kg i.p., n = 8) had no effect. Treatment with
2-ME (75 mg/kg p.o., n = 9) for 1 month suppressed the growth of a human
breast carcinoma in mice by 60% without toxicity. Recognition of the antiangiogenic and antitumor properties of
2-ME and
Taxol may be crucial in planning clinical applications to angiogenesis-dependent diseases.