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Background: To date, few single agent anti-angiogenic agents have entered into clinical use. However, there has been success in combining anti-angiogenic agents with conventional chemotherapy. Combining both activities in a single molecule will potentially generate a potent anti-cancer drug.

Materials and Methods: To assess the in vivo efficacy, mice bearing MDA-MB-231 xenografts (80-100 mm3) were treated for 28 days and tumor measurements taken weekly. At the end of the study the tumors were dispersed and the cell suspension used for cell cycle analysis and apoptosis quantification. Anti-angiogeneic activity was measured by tumor von Willebrand's factor IHC and further assessed using the Matrigel plug mouse model. In vitro cell cycle arrest and apoptosis were assessed by FACS. In vitro angiogenesis was evaluated using a co-culture model of human fibroblasts and endothelial cells.

Results: The two compounds 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE) and 2-ethylestradiol-3,17,O,O-bis-sulfamate (2-EtE2bisMATE) are efficacious by daily oral administration, with 20 mg/kg 2-MeOE2bisMATE and 40 mg/kg 2-EtE2bisMATE completely inhibiting tumor growth in contrast to 2-MeOE2. Paclitaxel and vinorelbine also inhibited tumor growth, however both must be given i.v. and only 3 times a week due to toxicity. Using an innovative ex vivo methodology we clearly demonstrate cell cycle arrest and apoptosis in vivo. These compounds are also anti-angiogenic in vitro and in vivo.

Discussion: Here we describe and characterise two potent anti-cancer compounds which combine anti-tumor and anti-angiogenic activities in one orally bioavailable molecule. These properties may translate into a significant clinical improvement over existing agents, such as the Taxanes.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA