Abstract
Sulfamoylation of 2‐methoxyestrone (2‐MeOE1) was shown previously to enhance its potency as an anti‐proliferative agent against breast cancer cells. We have examined the ability of a series of 2‐methoxyestradiol (2‐MeOE2) and 2‐ethylestradiol (2‐EtE2) sulfamates to inhibit angiogenesis in vitro__.__ 2‐MeOE2 bis‐sulfamate and 2‐EtE2 sulfamate were potent inhibitors of human umbilical vein endothelial cell (HUVEC) proliferation with IC~50~ values of 0.05 μM and 0.01 μM, respectively. A novel co‐culture system, in which endothelial cells were cultured in a matrix of human dermal fibroblasts, was also used to assess the anti‐angiogenic potential of these drugs. In this system endothelial cells proliferate and migrate through the culture matrix to form tubule structures. Whereas 2‐MeOE2 (1.0 μM) caused a small reduction in tubule formation, both 2‐MeOE2 bis‐sulfamate (0.1 μM) and 2‐EtE2 sulfamate (0.1 μM) almost completely abolished tubule formation. 2‐MeOE2 bis‐sulfamate and 2‐EtE2 sulfamate both induced BCL‐2 phosphorylation, p53 protein expression and apoptosis in HUVECs. Microarray analysis of a limited number of genes known to be involved in the angiogenic process did not show any gross changes in cells treated with the 2‐substituted estrogens. The sulfamoylated derivatives of 2‐MeOE2 and 2‐EtE2 are potent inhibitors of in vitro angiogenesis and both compounds should have therapeutic potential. © 2004 Wiley‐Liss, Inc.