2-methoxyestradiol blocks estrogen-induced rat pituitary tumor growth and tumor angiogenesis: Possible role of vascular endothelial growth factor

Natural and synthetic estrogens have been associated with several types of human and animal cancers including prolactin-secreting pituitary tumors in Fischer 344 rats. These prolactin-secreting tumors are highly angiogenic and their growth is angiogenic dependent In the present study we have utilized this model to evaluate the effect of 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite that is a potent inhibitor of endothelial cell proliferation in vitro, on estrogen-induced pituitary tumor growth and angiogenesis. Adult female rats were implanted (subcutaneously) with a silastic capsule containing estradiol-17 beta (E-2). After seven days of constant E2 exposure animals were injected (sc) daily with 25 mg/kg of 2-ME and killed either three or 8 days later. Changes in pituitary weight and proliferating cell nuclear antigen (PCNA) labeling index indicated growth while degree of angiogenesis was determined immunohistochemically using factor VIII related antigen. The results indicate that 2-ME inhibited estrogen-induced lactotroph growth by 32% and tumor angiogenesis by 89%. Furthermore, vascular endothelial growth factor (VEGF) expression, evaluated by immunohistochemical analysis, was down-regulated concomitant with tumor angiogenic suppression. These studies suggest that 2-ME may have therapeutic potential for hormone-induced cancer and that its angiostatic activity may be modulated through down-regulation of VEGF expression.