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Clinical Trial of Selenium and Prostate Biomarkers

硒和前列腺生物标志物的临床试验

基本信息

批准号：
7768495
负责人：
James Marshall
金额：
$ 28.41万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-10 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7768495
关键词：
American Androgen Receptor Androgens Benign Biological Markers Cancer Patient Cancer Prevention Trial Cell Cycle Chemoprevention Chemopreventive Agent Clinical Trials Core Biopsy Desmosterol Disease Dose Down-Regulation Enzymes Freezing Gene Targeting Genes Human Human Glandular Kallikrein 2 Laboratories Lead Living Costs Malignant neoplasm of prostate Metabolism Nutritional Oxidoreductase Patient Schedules Peripheral Phenotype Placebos Population Prevention Prostate Prostate-Specific Antigen Prostatectomy Prostatic Prostatic Intraepithelial Neoplasias Quality of life Randomized Receptor Signaling Sampling Selenium Selenomethionine Signal Transduction Supplementation Testing Tissues Vitamin E cancer therapy experience hepatocyte nuclear factor 6 human data in vivo killings men mortality response thiol S-methyltransferase transcription factor

项目摘要

In spite of progress against prostate cancer (PC), treatment of the disease still exacts significant financial and quality-of-life costs. And, as treatment is not always effective, PC still kills some 30,000 American men each year. Prevention, including chemoprevention, remains a potentially attractive approach. Among the numerous chemopreventive agents, selenium appears promising; its chemopreventive utility was strongly suggested by the Nutritional Prevention of Cancer (NPC) trial, led for several years by the PI. In the NPC trial, men assigned to supplementation by 200 meg selenium/day experienced 50% lower PC mortality than men assigned to placebo; these results helped to lead to the trials of selenium for men with high grade prostatic intraepithelial neoplasia (HGPIN) and to the Selenium and Vitamin E Chemoprevention Trial (SELECT). The mechanisms underlying the chemopreventive action of selenium in PC are poorly understood. Results from our laboratory indicate that selenium alters androgen signaling, with decreased expression of the androgen receptor (AR), and AR target genes such as prostate-specific antigen (PSA), kallikrein 2 (KLK2), 24-dehydrocholesterol reductase (DHCR24), cell division cycle 6 (CDC6), and hepatocyte nuclear factor 3a (HNF3a). These findings need to be tested in human populations; we propose to do this by randomizing prostate cancer patients scheduled for brachythrapy and prostatectomy to pretreatment supplementation by daily dose of 400 meg selenomethionine, or to placebo. After 8-9 weeks of supplementation, at treatment, biopsy core samples will be obtained from the peripheral zone of the prostate and frozen, then microdissected, with benign tissue analyzed by qRT-PCR for expression of AR as the primary endpoint, and for PSA, KLK2, DHCR24, CDC6 and HNFSa as secondary endpoints. In addition, we will explore the hypothesis that the activity of thiol methyltransferase, a key enzyme in selenium metabolism, correlates with the response to selenomethionine supplementation. This study will provide key in vivo, human data on the mechanisms of selenium's action in the prostate, and greatly help interpret the results of the important chemoprevention trials such as HGPIN and SELECT.

尽管前列腺癌(PC)的治疗取得了进展，但该病的治疗仍然非常重要。财务和生活质量成本。而且，由于治疗并不总是有效的，PC仍导致约30,000人死亡每年都有美国男人。预防，包括化学预防，仍然是一个潜在的有吸引力的问题接近。在众多的化学预防药物中，硒显得很有前途；它的化学预防作用营养预防癌症(NPC)试验强烈建议，该试验由圆周率。在NPC试验中，被分配每天补充200兆克硒的男性经历了50% 与服用安慰剂的男性相比，PC死亡率更低；这些结果有助于硒的试验对男性高级别前列腺上皮内瘤变(HGPIN)及对硒和维生素E的影响化学预防试验(SELECT)。硒在PC中的化学预防作用机制尚不清楚。我们实验室的结果表明，硒改变了雄激素信号，并减少了表达雄激素受体(AR)和AR靶基因，如前列腺特异性抗原(PSA)、激肽释放酶 2(KLK2)、24-脱氢胆固醇还原酶(DHCR24)、细胞分裂周期6(CDC6)和肝细胞核因子3a(HNF3a)。这些发现需要在人类群体中进行测试；我们建议这样做这是通过将计划接受近距离前列腺切除术和前列腺切除术的前列腺癌患者随机分为预先补充每日400兆克硒蛋氨酸，或服用安慰剂。8-9年后补充数周后，在治疗时，将从周围区域获取活检核心样本冰冻的前列腺组织，然后进行显微解剖，并用qRT-PCR分析良性组织 AR为主要终点，PSA、KLK2、DHCR24、CDC6和HNFSa为表达次要端点。此外，我们还将探讨以下假设：硫醇的活性甲基转移酶是硒代谢中的一个关键酶，与对补硒蛋氨酸。这项研究将提供体内和人体内关于硒在前列腺中作用机制的关键数据，并极大地帮助解释了重要的化学预防试验的结果，如HGPIN和选择。