Time-dependent and bidirectional effect of oxidative stress - a missing piece of the free radical theory of cancer and its potential implications

氧化应激的时间依赖性和双向效应——癌症自由基理论的缺失部分及其潜在影响

• 批准号: 9887609
• 负责人: Qingxia Chen
• 金额: $ 70.35万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887609
• 关键词: 8-hydroxyguanosine; Accounting; Advanced Malignant Neoplasm; Aftercare; American; Animal Model; Antioxidants; Asians; Biochemical; Biological; Blood; Cancer Patient; Cancer Prognosis; Cancer Survivor; Chemoprevention; Chemopreventive Agent; Chinese People; Clinical; Cohort Studies; Colorectal Cancer; DNA; Development; Diagnostic; European; F2-Isoprostanes; Follow-Up Studies; Free Radicals; Health; Human; In Vitro; Intake; Joints; Lead; Link; Lipid Peroxidation; Longterm Follow-up; Malignant Neoplasms; Measurement; Measures; Molecular; Nature; Oncogenic; Oncologist; Outcome; Oxidative Stress; Participant; Patient Care; Patients; Phase; Pilot Projects; Population; Publishing; RNA; Radiation therapy; Randomized Clinical Trials; Research Personnel; Risk; Role; Sample Size; Sampling; Science; Supplementation; System; Target Populations; Time; Urine; Woman; Women' s Health; Work; cancer cell; cancer risk; cancer survival; carcinogenesis; cell injury; chemotherapy; cohort; colorectal cancer prevention; colorectal cancer risk; cytotoxic; design; diet and cancer; epidemiology study; follow-up; hazard; healing; insight; male health; novel; oxidation; oxidative damage; sex; theories; tumor; tumorigenesis

SUMMARY Conventional wisdom says that antioxidants should lower cancer risk by neutralizing cell- damaging, cancer-causing oxidative stress. However, despite the compelling biochemical evidence that ties oxidative damage to carcinogenesis for in vitro systems, almost all large randomized clinical trials have shown that antioxidant supplementation provides no clear benefit and even increases cancer risk. These disappointing and seemingly contradictory results have puzzled the public and researchers for decades. Even more controversial is whether antioxidant supplementation is safe and effective for cancer survivors. An estimated 15.5 million Americans in 2016 were cancer survivors, and up to 81% of them used antioxidant supplements to promote healing. However, we do not understand whether and to what extent post-treatment oxidative stress is associated with cancer prognosis. We recently conducted a molecular epidemiological study of colorectal cancer (CRC). We found the first piece of evidence in humans that the association between oxidative stress and CRC risk was bidirectional, with both beneficial and deleterious effects. Moreover, these bidirectional effects were time-dependent. Specifically, in earlier phases of cancer development, high oxidative stress was associated with increased risk of CRC, whereas in later phases, it was associated with decreased risk. Correspondingly, we found that the association between antioxidant intake and CRC risk was also time- dependent and varied by baseline oxidative stress. In the pilot study, we found that among patients with more advanced cancer, their systemic levels of oxidative stress were actually lower. Furthermore, cancer patients with higher post-treatment levels of oxidative stress had odds of living longer, after comprehensively adjusting for clinical parameters. In this proposed study, we will conduct a large case-cohort study, building upon three Asian and European cohorts to determine whether our novel findings—the time-dependent and bidirectional effects of oxidative stress and antioxidants on CRC, first observed in Chinese women (discovery phase)—can be replicated in both sexes and in different ethnic populations (replication phase). Comprehensive assessments of oxidative stress in pre-diagnostic urine samples will be performed. We will also conduct a follow-up study of CRC cases from whom both pre-diagnostic and post-treatment urine samples have been collected. We will examine whether higher levels of systemic post-treatment oxidative stress are associated with better CRC survival, while comprehensively accounting for pre-diagnostic oxidative stress and other clinical parameters. We expect that this study, with its focus on the time-dependent and bidirectional association between oxidative stress and CRC, will provide novel insights into the role of oxidative stress in carcinogenesis, the first evidence linking oxidative stress and clinical outcomes of CRC, and much needed information for identification of population subsets for chemoprevention. Thus, this study will have high translational potential to lead to tailored strategies for CRC prevention and patient care.

概括 传统智慧说，抗氧化剂应通过中和细胞来降低癌症风险 破坏性，引起癌症的氧化物应激。然而，尽管有令人信服的生化证据 体外系统对癌变的氧化损害，几乎所有大型随机临床试验都显示 补充抗氧化剂没有明显的益处，甚至增加了癌症的风险。这些 几十年来，令人失望和看似矛盾的结果困扰了公众和研究人员。甚至 更具争议的是补充抗氧化剂是否对癌症存活是安全有效的。 2016年估计有1,550万美国人是癌症的存活，其中多达81％使用抗氧化剂 补充以促进康复。但是，我们不明白治疗后是否以及在何种程度上 氧化应激与癌症预后有关。我们最近进行了一项分子流行病学研究 结直肠癌（CRC）。我们发现人类中的第一个证据表明 氧化应激和CRC风险是双向的，具有有益和有害影响。而且，这些 双向效应是时间依赖性的。具体而言，在癌症发展的早期阶段，高氧化 压力与CRC的风险增加有关，而在以后的阶段，它与下降有关 风险。相应地，我们发现抗氧化剂摄入与CRC风险之间的关联也很时光 - 依赖性和因基线氧化应激而变化。在试点研究中，我们发现在有更多的患者中 晚期癌症，其全身氧化应激水平实际上较低。此外，癌症患者 经过全面调整后，氧化应激水平较高的氧化应激水平的寿命更长 用于临床参数。在这项拟议的研究中，我们将进行一项大型病例研究，以三个为基础 亚洲和欧洲人群来确定我们的新发现（时间依赖性和双向）是否 氧化应激和抗氧化剂对CRC的影响，首先在中国妇女（发现阶段）观察到 - 可以 在性别和不同种族人口（复制阶段）中得到复制。综合的 将评估诊断前尿液样品中氧化应激。我们还将进行 诊断前和治疗后尿液样本的CRC病例的后续研究 集。我们将检查较高水平的全身治疗后氧化应激是否与 具有更好的CRC存活率，同时全面考虑了诊断前的氧化应激和其他 临床参数。我们期望这项研究侧重于时间依赖和双向 氧化应激与CRC之间的关联将为氧化应激在 致癌作用，第一个与CRC的氧化应激和临床结局联系起来的证据，急需 用于识别种群化学预防的种群子集的信息。那，这项研究将有很高的 转化潜力，导致针对CRC预防和患者护理的量身定制策略。