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: 7472860
• 负责人: KARAM E EL-BAYOUMY
• 金额: $ 42.83万
• 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/7472860
• 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; End Point; Europe; European; Event; F2-Isoprostanes; Future; Glutathione; Goals; Hispanics; Human; Incidence; Inflammation; Intervention Trial; Invasive; Knowledge; Letters; Lipids; Literature; Lobe; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measurement; Metabolism; Molecular; Numbers; 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; Purpose; Randomized; Rattus; Reporting; Research; Risk; Risk Factors; Risk Marker; Rodent; Role; Scientist; Selenium; Selenomethionine; Series; Serum; Side; Site; Stanolone; Supplementation; Testing; Testosterone; Thinking; Time; Trace Elements; Urologist; Yeasts; age group; base; cancer chemoprevention; cancer prevention; cancer risk; carcinogenesis; caucasian American; day; dietary supplements; insight; interest; male; men; men' s group; novel; oxidation; oxidative DNA damage; pre-clinical; preclinical study; programs; prostate cancer prevention; protective effect; selenium deficiency; urinary; young adult; 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; End Point; Europe; European; Event; F2-Isoprostanes; Future; Glutathione; Goals; Hispanics; Human; Incidence; Inflammation; Intervention Trial; Invasive; Knowledge; Letters; Lipids; Literature; Lobe; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measurement; Metabolism; Molecular; Numbers; 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; Purpose; Randomized; Rattus; Reporting; Research; Risk; Risk Factors; Risk Marker; Rodent; Role; Scientist; Selenium; Selenomethionine; Series; Serum; Side; Site; Stanolone; Supplementation; Testing; Testosterone; Thinking; Time; Trace Elements; Urologist; Yeasts; age group; base; cancer chemoprevention; cancer prevention; cancer risk; carcinogenesis; caucasian American; day; dietary supplements; insight; interest; male; men; men' s group; novel; oxidation; oxidative DNA damage; pre-clinical; preclinical study; programs; prostate cancer prevention; protective effect; 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）是男性与癌症相关死亡的第二大原因。衰老是主要的危险因素，非洲裔美国人（AA）的风险高于白人美国人（WA）。美国癌症协会估计，将有9,879名（0-39岁），39岁（40-59岁）和7（60-79岁）中有1个（年龄在60-59岁）中被诊断为侵入性PC。老年人会出现痕量元素缺陷（例如硒）；最近，我们表明年龄较大的大鼠也会出现硒缺乏症。硒缺乏增加了氧化应激和癌症的风险。富含硒的酵母（SY）的补充已证明可以预防人类的前列腺癌。然而，硒的剂量和形式是年龄的函数以及作用机理，尚待阐明。在一项试点研究中，我们表明SY（240 5G/天9个月）抑制了氧化应激，可降低健康男性的PSA水平<40岁。我们首次报告SY还抑制1-1抗胰蛋白酶（ATT）；据报道，该蛋白在PC患者中过度表达，其水平与PSA水平正相关，并且AA中的水平高于WA。我们的假设是，必须根据年龄的函数对硒剂量量身定制，以有效地抑制不同年龄组的氧化应激和其他风险标志，并且这种抑制作用部分是由于硒与氧化还原敏感蛋白的相互作用，包括可能参与细胞增殖和/或凋亡的ATT。 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个月以来，在各个年龄段的AA和WA男子（25名男子）中：年轻人（20-39岁），成熟的（40-59岁）和老年人（60-79岁）SM，目前正在美国的主要临床试验中使用。 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血浆3-硝基酪氨酸水平和4。氧化还原敏感蛋白（例如ATT）的血浆蛋白质组谱。结果将提供有关形式和剂量的见解，这些形式和剂量可能有助于硒的保护作用。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，结果将提供新型的生物标志物，可用于当前和未来的硒干预试验。公共卫生相关性：在美国，前列腺癌（PC）是男性与癌症相关死亡的第二大原因。衰老是主要的危险因素，非裔美国人的风险要高于白人美国人。硒已被证明可以预防人类中的PC。然而，硒的剂量和形式是年龄的函数以及作用机理，尚待阐明。这些研究的结果对于硒剂（形式和剂量）的进一步开发和适当的定制是年龄的函数至关重要的。此外，这项研究将提供新型的生物标志物，可用于早期检测该疾病，以及在目前在世界上（包括美国选择）的主要临床硒干预试验中。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。