Reduced Levels of 5-alpha Reductase 2 in Adult Prostate Tissue: Implications for

成人前列腺组织中 5-α 还原酶 2 水平降低：对以下疾病的影响

• 批准号: 8237826
• 负责人: Aria F Olumi
• 金额: $ 38.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237826
• 关键词: Accounting; Adrenergic alpha-Antagonists; Adult; Affect; American; Androgens; Apoptosis; Benign; Benign Prostatic Hypertrophy; Bladder; Cell Line; Chemoprevention; Chronic; Clinical Research; Complication; CpG Islands; CpG dinucleotide; Disease; Disease Progression; Elderly man; Enzymes; Epithelial; Epithelial Cells; Expenditure; Finasteride; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Growth; Growth and Development function; Hair follicle structure; Healthcare; Human; Island; Lead; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Medical; Methylation; Obstruction; Office Visits; Operative Surgical Procedures; Oxidoreductase; Patient observation; Patients; Pattern; Pelvis; Pharmaceutical Preparations; Promoter Regions; Prostate; Prostatic; Proteins; Repression; Research; Resistance; Risk; Sampling; Secondary to; Skin; Smooth Muscle Myocytes; Specimen; Stanolone; Strategic Planning; Stromal Cells; Symptoms; Testosterone; Testosterone 5-alpha-Reductase; Therapeutic; Tissues; United States National Institutes of Health; Urethra; age related; base; cholestenone 5 alpha-reductase; design; improved; inhibitor/antagonist; lower urinary tract symptoms; men; promoter; prostate transurethral resection; protein expression; resistance mechanism; therapy resistant; treatment strategy; urinary tract obstruction

DESCRIPTION (provided by applicant): 5-1 reductase 2 inhibitors are commonly used for medical management of patients with obstructive uropathy secondary to benign prostatic hyperplasia (BPH). Finasteride, the most commonly used 5-1 reductase inhibitor, is prescribed to 8.2 million American men. Based on our preliminary results, we estimate that 2.37 million of those men are resistant to its therapeutic action, because they do not express its intended target enzyme, 5-1 reductase 2, accounting for $640 million in annual health care spending. Despite its common use, mechanisms accounting for resistance to Finasteride are not understood. To explore why some patients are resistant to the widely used 5-1 reductase type 2 inhibitor, we evaluated the degree of expression of 5-1 reductase 2 in human prostate tissues. We found that there is a wide variability of expression of 5-1 reductase 2 in human prostate samples with 30% of different samples lacking expression of the protein. Since methylation of the CpG dinucleotide islands in the promoter region of genes has been associated with regulation of genes, we investigated whether the 5-1 reductase gene contains CpG islands. We found that the 5-1 reductase 2 promoters contains a rich CpG island and in fact the CpG island is methylated in many prostate cell lines which do not express 5-1 reductase 2. In addition, there is a strong correlation between methylation of 5-1 reductase 2 promoter regions and absence of 5-1 reductase 2 in human prostate samples. Therefore, we hypothesize that methylation of the promoter region of 5-1 reductase 2 gene is associated with reduced expression of the protein, which can lead to stagnant or suppressed prostatic growth in adulthood, and possibly accounting for resistance to 5-1 reductase 2 inhibitor therapies. This clinical study is designed to explore the heterogeneous growth pattern of adult human prostates as related to expression of 5-1 reductase 2, and to evaluate the mechanisms of resistance to 5-1 reductase 2 inhibitions. The specific aims are: Specific Aim #1. To determine whether methylation of 5-1 reductase 2 promoter region is associated with repression of 5-1 reductase 2 protein in human prostate tissue. Specific Aim #2. To determine whether methylation of 5-1 reductase 2 promoter is associated with decreased prostatic growth rates. Specific Aim #3. To determine whether methylation of 5-1 reductase 2 promoter and reduced expression of 5-1 reductase 2 is associated with resistance to Finasteride in management of BPH. Our proposal is well-aligned with NIH/NIDDK's Prostate Research Strategic Plan. The findings will have broad implications for chronic use of 5-1 reductase 2 inhibitors for BPH, and also in newly suggested strategies for chemoprevention of prostate cancer. Recognition of mechanisms that regulate expression of 5-1 reductase 2 will lead to identification of newer compounds and better targeted therapies for BPH and reduce the rates of invasive therapies for this benign condition. PUBLIC HEALTH RELEVANCE: Inhibition of 5-1 reductase, the enzyme responsible for development and growth of prostate, is commonly utilized for treatment of patients suffering from lower urinary tract symptoms secondary to benign prostatic hyperplasia. However, 30% of human prostates do not express 5-1 reductase. Here we investigate mechanisms that may account for different prostate growth patterns and resistance to therapy in adult men.

描述(由申请人提供)：5-1还原酶2抑制剂通常用于良性前列腺增生症(BPH)继发梗阻性尿路疾病患者的医疗管理。最常用的5-1还原酶抑制剂非那雄胺被开给820万美国男性。根据我们的初步结果，我们估计这些男性中有237万人对其治疗作用具有抵抗力，因为他们不表达其预期的目标酶5-1还原酶2，占每年医疗保健支出的6.4亿美元。尽管它被广泛使用，但对非那雄胺耐药的机制尚不清楚。为了探索一些患者对广泛使用的5-1还原酶2抑制剂产生耐药性的原因，我们评估了5-1还原酶2在人类前列腺组织中的表达程度。我们发现，5-1还原酶2在人前列腺组织中的表达存在很大的差异性，30%的不同样本缺乏该蛋白的表达。由于基因启动子区域CpG二核苷酸岛的甲基化与基因调控有关，我们研究了5-1还原酶基因是否含有CpG岛。我们发现5-1还原酶2启动子含有丰富的CpG岛，事实上在许多不表达5-1还原酶2的前列腺细胞系中CpG岛发生甲基化。此外，5-1还原酶2启动子区的甲基化与人前列腺组织中5-1还原酶2的缺失有很强的相关性。因此，我们推测5-1还原酶2基因启动子区域的甲基化与该蛋白的表达减少有关，这可能导致成年后前列腺生长停滞或受到抑制，并可能解释对5-1还原酶2抑制剂治疗的抵抗。本临床研究旨在探讨成人前列腺异质性生长模式与5-1还原酶2表达的关系，并探讨其抵抗5-1还原酶2抑制的机制。其具体目的是：特定目的1.确定5-1还原酶2启动子区甲基化是否与5-1还原酶2蛋白在人前列腺组织中的抑制有关。具体目的#2.确定5-1还原酶2启动子甲基化是否与前列腺生长速度减慢有关。具体目的#3.确定5-1还原酶2启动子甲基化和5-1还原酶2表达降低是否与良性前列腺增生症对非那雄胺耐药有关。我们的建议与NIH/NIDDK的前列腺研究战略计划非常一致。这一发现将对长期使用5-1还原酶2抑制剂治疗BPH以及新提出的前列腺癌化学预防策略具有广泛的意义。对调节5-1还原酶2表达的机制的认识将导致发现新的化合物和更好的针对BPH的靶向治疗，并降低这种良性疾病的侵入性治疗的比率。 公共卫生相关性：抑制5-1还原酶，负责前列腺发育和生长的酶，通常用于治疗继发于良性前列腺增生症的下尿路症状的患者。然而，30%的人类前列腺不表达5-1还原酶。在这里，我们研究了成年男性不同的前列腺生长模式和治疗抵抗的机制。