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;衰老是主要风险因素，非洲裔美国人（AA）的风险高于白色美国人（WA）。美国癌症协会估计，9,879人中有1人（0-39岁），39人中有1人（40-59岁），7人中有1人（60-79岁）将被诊断为侵袭性PC。老年人会出现微量元素缺乏症（例如，最近，我们发现老年大鼠也会出现硒缺乏症。硒缺乏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，硒的剂量和形式作为年龄的函数，以及作用机制仍有待阐明。在一项初步研究中，我们发现SY（240 5g/天，持续9个月）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还能抑制1-1抗胰蛋白酶（ATT）;据报道，这种蛋白质在PC患者中过度表达，其水平与PSA水平呈正相关，AA高于WA。我们的假设是，硒剂量必须根据年龄进行调整，以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氧化还原敏感蛋白（包括ATT）的相互作用，这些蛋白可能参与细胞增殖和/或凋亡。为了验证我们的假设，我们将进行一项双盲、随机、安慰剂对照的临床试验，以硒代蛋氨酸（SM=200 5g/d）和SY（240 5g/d和350 5g/d）的形式补充硒 较高剂量将递送200 μ g/天的SM;（SY中SM的可变性[SelenoExcell，Cypress Co.，Fresno，CA]在不同年龄组（25名男性/组）中的健康AA和WA男性中持续9个月低于3%：年轻（20-39岁），成熟（40-59岁）和老年（60-79岁）成人。SM目前正用于美国的一项主要临床试验（SELECT），SY用于欧洲的试验（PRECISE）;结果将在2013年及以后公布。具体来说，我们将确定补充硒对以下方面的影响：1。血浆（顺应性）和尿（生物利用度）硒水平和形式，2.风险生物标志物 PSA水平和睾酮代谢，3。氧化应激生物标志物 血液谷胱甘肽（GSH）和蛋白结合GSH（bGSH）、尿8-羟基-22-脱氧鸟苷水平、尿和血浆F2-异前列烷水平和血浆3-硝基酪氨酸水平，和4.氧化还原敏感性蛋白质的血浆蛋白质组谱（例如，ATT）。研究结果将提供有关硒的形式和剂量的见解，这些形式和剂量可能有助于硒作为年龄的函数的保护作用。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，结果将提供可用于当前和未来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;衰老是主要风险因素，非洲裔美国人的风险高于白色美国人。硒已被证明可以保护人类免受PC的侵害;然而，硒的剂量和形式作为年龄的函数，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定制硒剂（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，并在目前正在世界上进行的主要临床硒干预试验中，包括美国的SELECT。总的来说，这里提出的研究对控制和预防男性PC至关重要。