Anti-angiogenic and anti-tumor activity of 2-methoxyestradiol sulfamate analogs in the MCF-7 breast cancer xenograft nude mouse model

4544 A better understanding of the tumorigenic process has led to the realization that to effectively treat cancers requires the development of drugs that are multi-targeting in their action. Our group has synthesized and evaluated 2-methoxyestradiol-3,17-bis-sulfamate (STX 140) and a novel 2-methoxy D-ring modified estradiol sulfamate analog (STX 641). In vitro studies have shown them to target and inhibit steroid sulfatase enzyme activity, microtubule polymerization, and angiogenesis. These compounds were evaluated in vivo for their multi-targeting effects by measuring anti-angiogenic and anti-tumor activity in the MCF-7 breast cancer xenograft nude mouse model. Adult female ICRF nude (nu/nu) mice were injected with 10x106 MCF-7 cells/0.1ml Matrigel subcutaneously and tumor growth was monitored weekly. When tumors reached 100-150mm3 in volume, mice were divided into control, STX 140 and STX 641 groups. Compounds were given 5 times per week (20mg/kg/day, p.o.) for a 3 week period; controls received vehicle only. Mice were injected intravenously with 0.1ml of 25mg/ml FITC-Dextran solution 20 minutes prior to killing to allow the visualization and quantification of tumor angiogenesis. Liver and tumor steroid sulfatase activities were also determined. Imaging showed that tumors in the control group had a well defined and structured vasculature, whereas in STX 140 and STX 641 treated animals the tumor vasculature was disrupted and ill defined. FITC quantification of tumor angiogenesis revealed that levels were significantly lower in STX 140 and STX 641 treated animals (40% and 60% respectively, ANOVA p