Banerjeei S K, Zoubine M N, Sarkar D K, Weston A P, Shah J H, Campbell D R
Cancer Research Unit, V.A. Medical Center, Kansas City,MO 64128, USA.
Anticancer Res. 2000 Jul-Aug;20(4):2641-5.
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-17beta (E2). 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.
天然雌激素和合成雌激素与多种人类及动物癌症有关，包括费希尔344大鼠的分泌催乳素的垂体肿瘤。这些分泌催乳素的肿瘤具有高度血管生成性，其生长依赖血管生成。在本研究中，我们利用该模型评估2-甲氧基雌二醇（2-ME）的作用，2-ME是一种内源性雌激素代谢产物，在体外是内皮细胞增殖的有效抑制剂，对雌激素诱导的垂体肿瘤生长和血管生成的影响。成年雌性大鼠皮下植入含17β-雌二醇（E2）的硅橡胶胶囊。在持续暴露于E2七天后，动物每天皮下注射25mg/kg的2-ME，并在三天或八天后处死。垂体重量和增殖细胞核抗原（PCNA）标记指数的变化表明生长情况，而血管生成程度则使用因子VIII相关抗原通过免疫组织化学方法测定。结果表明，2-ME抑制雌激素诱导的催乳细胞生长32%，抑制肿瘤血管生成89%。此外，通过免疫组织化学分析评估的血管内皮生长因子（VEGF）表达，随着肿瘤血管生成抑制而下调。这些研究表明，2-ME可能对激素诱导的癌症具有治疗潜力，并且其血管生成抑制活性可能通过下调VEGF表达来调节。
