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: 8715777
• 负责人: Aria F Olumi
• 金额: $ 38.06万
• 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/8715777
• 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（由申请方提供）：5-1还原酶2抑制剂通常用于继发于良性前列腺增生（BPH）的阻塞性尿路病患者的药物治疗。芬达是最常用的5-1还原酶抑制剂，被处方给820万美国男性。根据我们的初步结果，我们估计其中有237万人对它的治疗作用有抵抗力，因为他们不表达其预期的靶酶5-1还原酶2，占每年医疗保健支出的6.4亿美元。 尽管它的普遍使用，机制占耐芬替尼的不理解。为了探索为什么一些患者对广泛使用的5-1还原酶2型抑制剂耐药，我们评估了5-1还原酶2在人前列腺组织中的表达程度。我们发现，在人前列腺样品中5-1还原酶2的表达存在广泛的变异性，其中30%的不同样品缺乏该蛋白的表达。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，CpG岛在许多不表达5-1还原酶2的前列腺细胞系中被甲基化。此外，在人前列腺样品中，5-1还原酶2启动子区域的甲基化与5-1还原酶2的缺失之间存在强相关性。因此，我们假设5-1还原酶2基因启动子区的甲基化与蛋白质表达减少有关，这可能导致成年期前列腺生长停滞或抑制，并可能导致对5-1还原酶2抑制剂治疗的耐药性。本临床研究旨在探讨成人前列腺的异质性生长模式与5-1还原酶2表达的关系，并评估对5-1还原酶2抑制剂的抗性机制。具体目标是：具体目标#1。目的：探讨前列腺组织中5-1还原酶2启动子区甲基化是否与5-1还原酶2蛋白的抑制有关。具体目标#2确定5-1还原酶2启动子甲基化是否与前列腺生长速率降低相关。具体目标#3目的探讨5-1还原酶2基因启动子甲基化和5-1还原酶2基因表达降低是否与前列腺增生症患者对芬氟拉明耐药有关。 我们的建议与NIH/NIDDK的前列腺研究战略计划保持一致。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产生广泛的影响。对调节5-1还原酶2表达的机制的认识将导致对BPH的新化合物和更好的靶向治疗的鉴定，并降低这种良性疾病的侵入性治疗率。