Translational Research of Finasteride and Selenium Prevention of Prostate Cancer

非那雄胺和硒预防前列腺癌的转化研究

• 批准号: 7687536
• 负责人: CLEMENT C IP
• 金额: $ 107.04万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687536
• 关键词: Translational; Research; Finasteride; Selenium; Prevention

DESCRIPTION (provided by applicant): The objective of the program project is to develop a novel mechanism-driven strategy for prostate cancer prevention. The approach is based on suppressing androgen signal transduction at two different steps simultaneously by using finasteride to inhibit the formation of dihydrotestosterone and selenium to reduce androgen receptor (AR) expression. The program is built along a bench-to-bedside paradigm and consists of three highly integrated projects. Project 1 is to delineate how finasteride and selenium work cooperatively to modulate certain molecular events in controlling the clonal expansion of prostate cancer cells. Special emphasis is placed on the functional analysis of key targets and pathways responsible for the induction of apoptosis following treatment with finasteride/selenium. Microenvironmental hypoxia is frequently seen in a colony of proliferating cancer cells due to abnormalities of the vasculature. It is well known that hypoxia produces a variety of molecular changes as a selective pressure for survival. There is recent evidence suggesting that hypoxia facilitates AR activation and the transcription of androgen-responsive genes. The above process is mediated by a redox-regulating protein called peroxiredoxin-1, or Prx1. Prx1 is preferentially elevated in prostatic intraepithelial neoplasia and prostate cancer cells. Project 2 is to investigate the mechanism of hypoxia/Prxl stimulation of AR signaling and to assess the role of Prx1 in modifying the cancer control efficacy of finasteride/selenium. The findings of Projects 1 and 2 are critical to the interpretation of the clinical trial results of Project 3. A short-term intervention trial is proposed to verify the effect of finasteride/selenium on androgen target gene expression and apoptosis induction in prostate tissue samples obtained from pre-prostatectomy patients. A second objective of the trial is to determine whether a high level of Prx1 diminishes the sensitivity to finasteride/selenium intervention. Every year, approximately 230,000 new cases of prostate cancer are diagnosed in the US, and some 30,000 men will die of this disease. As a public health problem, prostate cancer engenders huge medical care and human suffering costs. Blocking the progression of small volume, low-grade neoplasia is increasingly being recognized as an important aspect of prostate cancer control. Our goal is to find a way of managing the disease at an early stage in order to prevent it from becoming clinical relevant.

描述（由申请人提供）：该计划项目的目标是开发一种新的机制驱动策略来预防前列腺癌。该方法基于同时抑制两个不同步骤的雄激素信号转导，使用非那雄胺抑制二氢睾酮和硒的形成，从而减少雄激素受体（AR）的表达。该计划是按照从实验室到临床的范例构建的，由三个高度集成的项目组成。项目 1 旨在描述非那雄胺和硒如何协同作用来调节某些分子事件，从而控制前列腺癌细胞的克隆扩张。特别强调非那雄胺/硒治疗后负责诱导细胞凋亡的关键靶点和途径的功能分析。由于脉管系统异常，在增殖的癌细胞群中经常出现微环境缺氧。众所周知，缺氧会产生多种分子变化，作为生存的选择压力。最近有证据表明缺氧促进 AR 激活和雄激素反应基因的转录。上述过程是由称为过氧化还原蛋白-1 (peroxiredoxin-1) 或 Prx1 的氧化还原调节蛋白介导的。 Prx1 在前列腺上皮内瘤变和前列腺癌细胞中优先升高。项目2是研究缺氧/Prxl刺激AR信号传导的机制，并评估Prx1在改变非那雄胺/硒的癌症控制功效中的作用。项目1和2的研究结果对于项目3临床试验结果的解读至关重要。拟进行一项短期干预试验，以验证非那雄胺/硒对获得的前列腺组织样本中雄激素靶基因表达和细胞凋亡诱导的影响来自前列腺切除术前的患者。该试验的第二个目标是确定高水平的 Prx1 是否会降低对非那雄胺/硒干预的敏感性。美国每年诊断出约 230,000 例前列腺癌新病例，约 30,000 名男性将死于这种疾病。作为一个公共健康问题，前列腺癌造成巨大的医疗保健和人类痛苦成本。阻止小体积、低级别肿瘤的进展越来越被认为是前列腺癌控制的一个重要方面。我们的目标是找到一种早期控制该疾病的方法，以防止其成为临床相关的疾病。