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: 7239373
• 负责人: CLEMENT C IP
• 金额: $ 103.1万
• 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/7239373
• 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）：该计划项目的目的是制定一种新型机制驱动的预防策略。该方法基于通过使用非那雄胺抑制二氢睾丸激素和硒的形成来降低雄激素受体（AR）表达，同时抑制了两个不同步骤的抑制雄激素信号转导。该计划是沿着基准式范式构建的，由三个高度集成的项目组成。项目1是为了描绘非那雄胺和硒如何合作调节某些分子事件，以控制前列腺癌细胞的克隆扩张。特别强调的是，对非那雄胺/硒治疗后负责诱导凋亡的主要目标和途径的功能分析。由于脉管系统的异常，在增殖的癌细胞的菌落中经常看到微环境缺氧。众所周知，缺氧会产生各种分子变化，作为生存的选择压力。最近有证据表明缺氧促进了AR激活和雄激素反应基因的转录。上述过程是由称为过氧蛋白-1或PRX1的氧化还原调节蛋白介导的。 PRX1在上皮内肿瘤和前列腺癌细胞中优先升高。项目2是为了研究缺氧/PRXL刺激AR信号传导的机制，并评估PRX1在修饰非那雄胺/硒的癌症控制功效中的作用。项目1和2的发现对于解释项目3的临床试验结果至关重要。提出了一项短期干预试验，以验证非那雄胺/硒对雄激素靶基因表达和凋亡诱导在前后切除术中获得的前列腺组织样品的影响。该试验的第二个目标是确定高水平的PRX1是否会降低对丁香胺/硒干预的敏感性。每年，在美国诊断出大约230,000例新的前列腺癌病例，大约30,000名男性将死于这种疾病。作为一个公共卫生问题，前列腺癌可导致巨大的医疗保健和人类痛苦成本。越来越多地认为阻止小体积的小体积进展，越来越多地被认为是前列腺癌控制的重要方面。我们的目标是找到一种在早期管理疾病的方法，以防止其变得临床相关。