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

总结 传统观点认为，抗氧化剂应该通过中和细胞来降低癌症风险- 破坏性的致癌氧化应激然而，尽管有令人信服的生化证据表明， 几乎所有的大型随机临床试验都表明， 补充抗氧化剂没有明显的益处，甚至会增加癌症风险。这些 几十年来，令人失望和看似矛盾的结果一直困扰着公众和研究人员。甚至 更有争议的是，抗氧化剂补充剂对癌症幸存者是否安全有效。一个 据估计，2016年有1550万美国人是癌症幸存者，其中高达81%使用抗氧化剂 补充剂，以促进愈合。然而，我们不知道是否以及在多大程度上后处理 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）。我们在人类身上发现了第一个证据， 氧化应激和CRC风险是双向的，既有有益的影响，也有有害的影响。而且这些 双向效应具有时间依赖性。具体而言，在癌症发展的早期阶段，高氧化性 压力与CRC风险增加相关，而在后期阶段，压力与CRC风险降低相关。 风险相应地，我们发现抗氧化剂摄入量和CRC风险之间的关系也是时间- 依赖于和变化的基线氧化应激。在初步研究中，我们发现， 在晚期癌症中，他们的全身氧化应激水平实际上更低。此外，癌症患者 治疗后氧化应激水平较高的患者在综合调整后， 临床参数。在这项拟议的研究中，我们将进行一项大型病例队列研究， 亚洲和欧洲队列，以确定我们的新发现-时间依赖性和双向性 氧化应激和抗氧化剂对CRC的影响，首次在中国女性中观察到（发现阶段）-可以 在两性和不同种族人口中复制（复制阶段）。全面 将进行诊断前尿样中氧化应激的评估。我们亦会进行一项 对诊断前和治疗后尿液样本均已 收集。我们将研究是否更高水平的全身性治疗后氧化应激与 具有更好的CRC生存率，同时综合考虑诊断前氧化应激和其他 临床参数我们希望这项研究，其重点是时间依赖性和双向性 氧化应激和CRC之间的关联，将提供新的见解氧化应激的作用， 致癌作用，第一个证据连接氧化应激和CRC的临床结果， 用于鉴定用于化学预防的群体亚群的信息。因此，这项研究将具有很高的 翻译潜力，从而为CRC预防和患者护理提供量身定制的策略。

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.