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[Cancer Research 57, 81-86, January 1, 1997]
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Inhibition of Angiogenesis and Breast Cancer in Mice by the Microtubule Inhibitors 2-Methoxyestradiol and Taxol1

Nancy Klauber, Sareh Parangi, Evelyn Flynn, Ernest Hamel and Robert J. D'Amato2

Department of Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115 [N. K., S. P., E. F., R. J. D.]; Department of Surgery, Boston University School of Medicine, Boston, Massachusetts 02118 [N. K.]; and Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892 [E. H.]

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.

1 This study was supported by a grant from Entremed, Inc. (Rockville, MD).

2 To whom requests for reprints should be addressed, at Children's Hospital, 300 Longwood Avenue, Ender's 1006, Boston, MA 02115. Phone: (617) 355-6234; Fax: (617) 355-7043; E-mail: damato_r@al.tch.harvard.edu.

Received 6/12/96. Accepted 10/31/96.




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