Reduced Levels of 5-alpha Reductase 2 in Adult Prostate Tissue and BPH Therapy

成人前列腺组织中 5-α 还原酶 2 水平的降低和 BPH 治疗

• 批准号: 8528577
• 负责人: Aria F Olumi
• 金额: $ 36.73万
• 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/8528577
• 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.

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（BPH）继发的梗阻性尿路病患者的医疗治疗。非那雄胺是最常用的 5-1 还原酶抑制剂，为 820 万美国男性处方。根据我们的初步结果，我们估计其中 237 万名男性对其治疗作用有抵抗力，因为他们不表达其预期的靶酶 5-1 还原酶 2，这相当于每年 6.4 亿美元的医疗保健支出。 尽管它被广泛使用，但对非那雄胺产生耐药性的机制尚不清楚。为了探究为什么一些患者对广泛使用的 5-1 还原酶 2 型抑制剂产生耐药性，我们评估了人类前列腺组织中 5-1 还原酶 2 的表达程度。我们发现人类前列腺样本中 5-1 还原酶 2 的表达存在很大差异，其中 30% 的不同样本缺乏该蛋白的表达。由于基因启动子区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岛被甲基化。此外，人前列腺样本中5-1还原酶2启动子区域的甲基化与5-1还原酶2的缺失之间存在很强的相关性。因此，我们假设 5-1 还原酶 2 基因启动子区域的甲基化与该蛋白表达的减少有关，这可能导致成年期前列腺生长停滞或受到抑制，并可能是对 5-1 还原酶 2 抑制剂治疗产生耐药性的原因。本临床研究旨在探索成人前列腺与 5-1 还原酶 2 表达相关的异质生长模式，并评估对 5-1 还原酶 2 抑制的抵抗机制。具体目标是： 具体目标#1。确定 5-1 还原酶 2 启动子区域的甲基化是否与人前列腺组织中 5-1 还原酶 2 蛋白的抑制相关。具体目标#2。确定 5-1 还原酶 2 启动子的甲基化是否与前列腺生长速率降低相关。具体目标#3。旨在确定 5-1 还原酶 2 启动子的甲基化和 5-1 还原酶 2 表达的降低是否与 BPH 治疗中对非那雄胺的耐药性相关。 我们的提案与 NIH/NIDDK 的前列腺研究战略计划非常一致。这些发现将对长期使用 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产生广泛影响。对调节 5-1 还原酶 2 表达的机制的认识将有助于识别更新的化合物和更好的 BPH 靶向治疗方法，并降低这种良性疾病的侵入性治疗率。