PROSTATIC DIFFERENTIATION & SEX HORMONE METABOLISM

前列腺分化

• 批准号: 3164278
• 负责人: Irwin Leav
• 金额: $ 15.68万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-09-30 至 1989-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3164278
• 关键词: androgen receptor; androgens; cell differentiation; electron microscopy; estradiol; estrogens; histochemistry /cytochemistry; hormone metabolism; hormone regulation /control mechanism; hormone related neoplasm /cancer; laboratory rat; prostate neoplasms; radioimmunoassay; radiotracer; sex hormones; testosterone; tritium

We have shown recently that simultaneous administration of testosterone (T) and estradiol-17Beta (E2) to intact Noble (Nb) rats for 16 wk induces intraductal dysplasia exclusively in the dorsal prostate (DP). Others have reported a significant number of these dysplasias subsequently evolve into invasive carcinoma. This sex hormone-induced lesion of Nb rats closely resembles ductal dysplasia in the human gland which is believed to be the antecedent lesion of prostatic carcinoma. While others report that the lesion can be induced by chronic treatment of rats with aromatizable T or estrone, per se, we have been unable to cause dysplasia following separate chronic treatment of animals with pharmacological doses of non-aromatizable 5Alpha-dihydrotestosterone (DHT) or E2. Therefore, our goal will be to determine if the pathogenesis of dysplasia can be linked to direct hormonal interactions of androgen-estrogen, or whether development of the pre-neoplastic lesion requires androgen-supported activation of estrogen to potentially carcinogenic metabolites; eg catechols. To investigate the role of estrogen in the genesis of dysplasia, we will utilize steroids with differing biological potencies and binding affinities for estrogen receptor (ER), and which differ in their capacity to form catechols. These estrogens will be administered for 16 wk to Nb rats, alone or in combination with DHT. Alterations in androgen-supported ER status and/or catechol formation in DP and hepatic microsomes will be assayed at varying time intervals during treatment. Temporal perturbations in specific biochemical parameters will be correlated with alterations in mitotic indices, and with hormone-mediated changes in differentiation found in the evolving dysplastic lesions. Our multidisciplinary studies will involve androgen and estrogen metabolism, receptor assays, immunohistochemistry, electron microscopy, and pathology. Our studies will be of particular importance to understanding critical factors involved in the pathogenesis of human prostatic carcinoma since sex steroids have long been suspected of playing a major role in the initation and progression of this neoplasm. The induction of dysplasia by combinations of E2 and T in our Nb rat model is of particular interest since imbalances in circulating sex steroids which could favor estrogen action at the target organ have been reported in agging men and in individuals with prostatic cancer.

我们最近已经表明，同时给予睾酮（T） 和雌二醇-17 β（E2）对完整的Noble（Nb）大鼠16 wk诱导 仅在背侧前列腺（DP）中存在导管内发育不良。 其他人已经 报道说，这些发育不良中有相当一部分随后演变成 浸润性癌 这种性别歧视引起的Nb大鼠的病变密切相关 类似于人类腺体中的导管发育不良， 前列腺癌前期病变。 虽然其他人报告说，病变可以诱导慢性治疗的 大鼠与芳香化T或雌酮本身，我们一直无法导致 单独慢性处理动物后的发育不良， 非芳香化5 α-二氢睾酮（DHT）的药理学剂量 或E2。 因此，我们的目标将是确定是否发病机制， 发育不良可能与以下因素的直接激素相互作用有关： 雄激素-雌激素，或是否发生肿瘤前病变 需要雄激素支持的雌激素激活， 致癌代谢物;如儿茶酚。 调查的作用 雌激素在发育不良的发生，我们将利用类固醇与 对雌激素受体的不同生物效力和结合亲和力 (ER)并且它们形成儿茶酚的能力不同。 这些 将雌激素单独或与其它药物一起给予Nb大鼠16周。 与DHT结合。 雄激素支持的ER状态改变和/或 DP和肝微粒体中的儿茶酚形成将在不同浓度下进行测定。 治疗期间的时间间隔。 特定时间的扰动 生物化学参数将与有丝分裂的改变相关。 指数，并与在分化中发现的细胞因子介导的变化， 发育不良性病变 我们的多学科研究将涉及 雄激素和雌激素代谢，受体测定，免疫组织化学， 电镜和病理学。 我们的研究将是特别重要的理解关键 人前列腺癌发病的性别因素 长期以来，人们一直怀疑类固醇在引发 以及肿瘤的进展 诱导发育不良， 在我们的Nb大鼠模型中，E2和T的组合特别令人感兴趣 因为循环中的性类固醇的不平衡可能有利于雌激素 在靶器官的行动已报告在男性和男性， 前列腺癌的症状有哪些