The influence of selenium on biomarkers of prostate cancer risk

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；老龄化是一个主要的风险因素，非裔美国人(AA)比白人美国人(WA)风险更高。美国癌症协会估计，每9879人(0-39岁)中有1人被诊断为侵袭性PC，39人(40-59岁)和7人(60-79岁)中有1人被诊断为侵袭性PC。老年人会患上微量元素缺乏症(如硒)；最近，我们发现老年大鼠也会患上缺硒症。缺硒会增加氧化应激和癌症的风险。富硒酵母(SY)的补充已被证明可以预防人类前列腺癌；然而，硒的剂量和形式随年龄的变化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)可以抑制氧化应激，降低40岁健康男性的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，且AA患者的水平高于WA患者。我们的假设是，硒的剂量必须是年龄的函数，才能有效地抑制不同年龄组的氧化应激和其他风险标记物，这种抑制在一定程度上是由于硒与氧化还原敏感蛋白(包括可能参与细胞增殖和/或凋亡的ATT)的相互作用。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，补充硒蛋氨酸(SM=200 5g/天)和SY(240 5g/天和350 5g/天，较高剂量将提供200 5g/天的SM；(SY[SelenoExcell，Cypress Co.，Fresno，CA]的SM变异性小于3%)对不同年龄组(25名男性/组)的健康AA和佤族男性进行9个月的检查：青年(20-39岁)、成熟(40-59岁)和老年(60-79岁)。SM目前正在美国的一项主要临床试验中使用(SELECT)，SY被用于欧洲的试验(PRECISE)；结果将在2013年及以后公布。具体地说，我们将确定补硒对以下方面的影响：1.血浆(顺应性)和尿硒(生物有效性)水平和形态，2.危险PSA水平和睾酮代谢的生物标记物，3.氧化应激生物标记物血液谷胱甘肽(GSH)和蛋白结合GSH(BGSH)，尿8-羟基-22-脱氧鸟苷水平，尿和血浆F2-异前列腺素水平，以及血浆3-硝基酪氨酸水平，以及4.氧化还原敏感蛋白(如ATT)的血浆蛋白质组图谱。这些结果将提供对硒的形式和剂量的洞察，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，其结果将提供新的生物标记物，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，非裔美国人比美国白人面临更高的风险。硒已被证明可以预防人类的前列腺癌；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。这些研究的结果对于进一步开发和适当调整作为年龄函数的硒制剂(形式和剂量)以达到更有效的化学预防计划的目的至关重要。此外，这项研究将提供新的生物标志物，可用于早期发现这种疾病，并用于目前世界上正在进行的主要临床硒干预试验，包括美国的SELECT。总而言之，这里提出的研究对于控制和预防男性前列腺癌是必不可少的。

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.