The influence of selenium on biomarkers of prostate cancer risk

硒对前列腺癌风险生物标志物的影响

• 批准号: 7659470
• 负责人: KARAM E EL-BAYOUMY
• 金额: $ 42.9万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-17 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659470
• 关键词: 1 year old; 3-nitrotyrosine; 8-hydroxy-2' -deoxyguanosine; Accounting; Adult; African American; Age; Age Reporting; Age-Years; Aged, 80 and over; Aging; Aging-Related Process; American; American Cancer Society; Anterior; Antioxidants; Apoptosis; Applications Grants; Area; Binding; Biological Availability; Biological Markers; Blood; Cancer Etiology; Cancer Patient; Caucasians; Caucasoid Race; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Research; Clinical Trials; Controlled Clinical Trials; Country; Cypress; DNA Markers; Data; Deoxyguanosine; Development; Diagnosis; Disease; Dose; Double-Blind Method; Early Diagnosis; Elderly; Elements; Epidemiology; Europe; European; Event; F2-Isoprostanes; Future; Glutathione; Goals; Hispanics; Human; Incidence; Inflammation; Intervention Trial; Knowledge; Letters; Lipids; Literature; Lobe; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measurement; Metabolism; Molecular; Oncologist; Outcome; Oxidation-Reduction; Oxidative Stress; Pilot Projects; Placebo Control; Placebos; Plasma; Play; Population; Predisposition; Property; Prostate; Prostate-Specific Antigen; Protein Binding; Protein C Inhibitor; Proteins; Proteomics; Public Health; Randomized; Rattus; Reporting; Research; Risk; Risk Factors; Risk Marker; Rodent; Role; Scientist; Selenium; Selenomethionine; Series; Serum; Side; Site; Stanolone; Supplementation; Testing; Testosterone; Time; Trace Elements; Urologist; Yeasts; age group; base; cancer chemoprevention; cancer prevention; cancer risk; carcinogenesis; caucasian American; dietary supplements; high risk; insight; interest; male; men; men' s group; novel; oxidation; oxidative DNA damage; pre-clinical; preclinical study; programs; prostate cancer prevention; protective effect; public health relevance; selenium deficiency; urinary; young adult

DESCRIPTION (provided by applicant): In the USA, prostate cancer (PC) is the second leading cause of cancer-related death in men; aging is a major risk factor and African Americans (AA) are at a higher risk than white Americans (WA). The American Cancer Society estimates that 1 in 9,879 (0-39 year-old), 1 in 39 (40-59 year-old), and 1 in 7 (60-79 year-old) will be diagnosed with invasive PC. Older people develop trace element deficiencies (e.g., selenium); recently, we showed that older rats also develop selenium deficiency. Selenium deficiency increases the risk of oxidative stress and cancer. Selenium-enriched yeast (SY) supplementation has been shown to protect against prostate cancer in humans; however, the dose and the form of selenium as a function of age, as well as the mechanism of action, remain to be elucidated. In a pilot study, we showed that SY (240 5g/day for 9 months) inhibits oxidative stress, reduces PSA levels in healthy men <40 years of age. We report for the first time that SY also inhibited 1-1 antitrypsin (ATT); this protein has been reported to be over expressed in PC patients and its levels are positively correlated with PSA levels and are higher in AA than WA. Our hypothesis is that selenium dose must be tailored as a function of age to be effective in inhibiting oxidative stress and other markers of risk in different age groups and such inhibition is, in part, due to selenium interaction with redox-sensitive proteins including ATT that may be involved in cell proliferation and/or apoptosis. To test our hypothesis, we will conduct a double-blind, randomized, placebo-controlled clinical trial of selenium supplementation in the form of selenomethionine (SM=200 5g/day) and SY (240 5g/day and 350 5g/day the higher dose will deliver 200 5g/day of SM; (the variability of SM in SY [SelenoExcell, Cypress Co., Fresno, CA] is less than 3%) for 9 months to healthy AA and WA men in various age groups (25 men/group): Young (20-39 year old), Matured (40-59 year old), and Old (60-79 year old) adults. SM is currently being used in a major clinical trial in the USA (SELECT) and SY is employed in the trial in Europe (PRECISE); the results will be known in 2013 and beyond. Specifically, we will determine the effect of selenium supplementation on: 1. plasma (compliance) and urinary (bioavailability) selenium levels and form, 2. biomarkers of risk PSA levels and testosterone metabolism, 3. biomarkers of oxidative stress blood glutathione (GSH) and protein bound GSH (bGSH), urinary 8-hydroxy- 22-deoxyguanosine levels, urinary and plasma F2-isoprostane levels, and plasma 3-nitrotyrosine levels, and 4. plasma proteomic profiles of redox-sensitive proteins (e.g., ATT). The results will provide insights into the form and dose that may contribute to the protective effect of selenium as a function of age. This study involves both basic scientists, a urologist and a clinical oncologist in the area of PC and the results will provide novel biomarkers that can be used in the current and future selenium intervention trials. PUBLIC HEALTH RELEVANCE: In the USA, prostate cancer (PC) is the second leading cause of cancer-related death in men; aging is a major risk factor and African Americans are at a higher risk than white Americans. Selenium has been shown to protect against PC in humans; however, the dose and the form of selenium as a function of age, as well as the mechanism of action, remain to be elucidated. The results of these studies are vital for the further development and appropriate tailoring of selenium agents (form and dose) as a function of age for the purpose of a more effective chemoprevention program. Furthermore, this study will provide novel biomarkers that can be used for early detection of this disease and in the major clinical selenium intervention trials that are currently being conducted in the world, including SELECT in the USA. Collectively, studies proposed here are essential to the control and prevention of PC in men.

描述（由申请人提供）： 在美国，前列腺癌 (PC) 是男性癌症相关死亡的第二大原因；老龄化是一个主要风险因素，非裔美国人 (AA) 的风险高于美国白人 (WA)。美国癌症协会估计，每 9,879 人中就有 1 人（0-39 岁）、每 39 人中有 1 人（40-59 岁）和七分之一（60-79 岁）将被诊断为侵袭性 PC。老年人会出现微量元素缺乏（例如硒）；最近，我们发现老年大鼠也会出现硒缺乏症。缺硒会增加氧化应激和癌症的风险。富硒酵母 (SY) 补充剂已被证明可以预防人类前列腺癌；然而，硒的剂量和形式与年龄的关系以及作用机制仍有待阐明。在一项初步研究中，我们表明 SY（240 5g/天，持续 9 个月）可以抑制氧化应激，降低 40 岁以下健康男性的 PSA 水平。我们首次报道SY还抑制1-1抗胰蛋白酶（ATT）；据报道，这种蛋白在 PC 患者中过度表达，其水平与 PSA 水平呈正相关，并且 AA 中的水平高于 WA。我们的假设是，硒剂量必须根据年龄进行调整，才能有效抑制不同年龄组的氧化应激和其他风险标志物，这种抑制部分是由于硒与包括 ATT 在内的氧化还原敏感蛋白的相互作用。可能参与细胞增殖和/或凋亡。为了检验我们的假设，我们将进行一项双盲、随机、安慰剂对照临床试验，以硒代蛋氨酸（SM=200 5g/天）和 SY（240 5g/天和 350 5g/天，较高者）的形式补充硒。剂量将提供 200 5g/天的 SM（SY 中 SM 的变异性 [SelenoExcell, Cypress Co., Fresno, CA]低于 3%），持续 9 个月，针对不同年龄组（25 名男性/组）的健康 AA 和 WA 男性：年轻（20-39 岁）、成熟（40-59 岁）和老年（60-79 岁） SM 目前正在美国进行一项大型临床试验（SELECT），而 SY 正在欧洲进行试验（PRECISE）；具体结果将在 2013 年及以后公布。补硒对以下方面的影响： 1. 血浆（依从性）和尿（生物利用度）硒水平和形式，2. 风险 PSA 水平和睾酮代谢的生物标志物，3. 氧化应激血谷胱甘肽 (GSH) 和蛋白结合 GSH 的生物标志物（ bGSH)、尿 8-羟基-22-脱氧鸟苷水平、尿和血浆 F2-异前列烷水平以及血浆3-硝基酪氨酸水平，以及 4. 氧化还原敏感蛋白（例如 ATT）的血浆蛋白质组谱。研究结果将深入了解硒的形式和剂量，这些形式和剂量可能有助于硒作为年龄函数的保护作用。这项研究涉及 PC 领域的基础科学家、泌尿科医生和临床肿瘤学家，其结果将提供可用于当前和未来的硒干预试验的新型生物标志物。公共卫生相关性：在美国，前列腺癌 (PC) 是男性癌症相关死亡的第二大原因；老龄化是一个主要的风险因素，非裔美国人的风险高于美国白人。硒已被证明可以预防人类 PC 的侵害；然而，硒的剂量和形式与年龄的关系以及作用机制仍有待阐明。这些研究的结果对于进一步开发和适当调整硒剂（形式和剂量）作为年龄的函数以实现更有效的化学预防计划至关重要。此外，这项研究将提供新的生物标志物，可用于早期检测这种疾病以及目前在世界范围内进行的主要临床硒干预试验，包括美国的 SELECT。总的来说，这里提出的研究对于控制和预防男性 PC 至关重要。