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

摘要 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、致癌的氧化应激。然而，尽管有令人信服的生化证据表明 氧化损伤对体外系统的致癌作用，几乎所有大型随机临床试验都表明 补充抗氧化剂不会带来明显的益处，甚至会增加癌症风险。这些 令人失望和看似矛盾的结果几十年来一直困扰着公众和研究人员。连 更具争议性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%的人使用抗氧化剂 能促进愈合的补充剂。然而，我们不知道治疗后是否以及在多大程度上 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)。我们在人类身上发现了第一个证据表明 氧化应激和结直肠癌的风险是双向的，既有有益的，也有有害的。此外，这些 双向效应是时间依赖的。具体地说，在癌症发展的早期阶段，高度氧化 压力与结直肠癌的风险增加有关，而在后期，它与减少有关。 风险。相应地，我们发现抗氧化剂摄入量与结直肠癌风险之间的关联也是时间- 依赖于氧化应激，并随基线氧化应激而变化。在试点研究中，我们发现，在患有更多 癌症晚期，他们全身的氧化应激水平实际上更低。此外，癌症患者 综合调整后，治疗后氧化应激水平越高，活得越久的几率越大 以获取临床参数。在这项拟议的研究中，我们将在三个基础上进行大型病例队列研究 亚洲和欧洲的队列来确定我们的新发现-依赖于时间和双向的 氧化应激和抗氧化剂对结直肠癌的影响，首次在中国女性中观察到(发现阶段)-CAN 在两性和不同族裔人群中复制(复制阶段)。全面 将对诊断前的尿样进行氧化应激评估。我们还将进行一次 诊断前和治疗后均取尿标本的大肠癌患者的随访研究 收好了。我们将研究较高水平的全身治疗后氧化应激是否与 结直肠癌存活率更高，同时综合考虑诊断前的氧化应激和其他 临床参数。我们期待这项研究，其重点是时间依赖和双向的 氧化应激与结直肠癌的关系，将为氧化应激在结直肠癌中的作用提供新的见解 致癌是将氧化应激与结直肠癌临床结局联系起来的第一个证据，也是亟需的 用于识别用于化学预防的种群子集的信息。因此，本研究将具有较高的研究价值。 翻译潜力导致为CRC预防和患者护理量身定做的战略。

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.