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 an d their growth is angiogenic dependent In the present study we have utilize d this model to evaluate the effect of 2-methoxyestradiol (2-ME), an endoge nous estrogen metabolite that is a potent inhibitor of endothelial cell pro liferation in vitro, on estrogen-induced pituitary tumor growth and angioge nesis. Adult female rats were implanted (subcutaneously) with a silastic ca psule containing estradiol-17 beta (E-2). After seven days of constant E2 e xposure animals were injected (sc) daily with 25 mg/kg of 2-ME and killed e ither 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 relate d antigen. The results indicate that 2-ME inhibited estrogen-induced lactot roph growth by 32% and tumor angiogenesis by 89%. Furthermore, vascular end othelial 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.