Emory University Rollins School of Public Health, Atlanta, GA 30322, USA.
Free Radic Biol Med. 2011 Sep 1;51(5):1068-84. doi: 10.1016/j.freeradbiomed.2011.05.018. Epub 2011 May 24.
The purpose of this review is to summarize the most important human clinical trials of antioxidants as cancer prevention agents conducted to date, provide an overview of currently ongoing studies, and discuss future steps needed to advance research in this field. To date there have been several large (at least 7000 participants) trials testing the efficacy of antioxidant supplements in preventing cancer. The specific agents (diet-derived direct antioxidants and essential components of antioxidant enzymes) tested in those trials included β-carotene, vitamin E, vitamin C, selenium, retinol, zinc, riboflavin, and molybdenum. None of the completed trials produced convincing evidence to justify the use of traditional antioxidant-related vitamins or minerals for cancer prevention. Our search of ongoing trials identified six projects at various stages of completion. Five of those six trials use selenium as the intervention of interest delivered either alone or in combination with other agents. The lack of success to date can be explained by a variety of factors that need to be considered in the next generation research. These factors include lack of good biological rationale for selecting specific agents of interest; limited number of agents tested to date; use of pharmacological, rather than dietary, doses; and insufficient duration of intervention and follow-up. The latter consideration underscores the need for alternative endpoints that are associated with increased risk of neoplasia (i.e., biomarkers of risk), but are detectable prior to tumor occurrence. Although dietary antioxidants are a large and diverse group of compounds, only a small proportion of candidate agents have been tested. In summary, the strategy of focusing on large high-budget studies using cancer incidence as the endpoint and testing a relatively limited number of antioxidant agents has been largely unsuccessful. This lack of success in previous trials should not preclude us from seeking novel ways of preventing cancer by modulating oxidative balance. On the contrary, the well demonstrated mechanistic link between excessive oxidative stress and carcinogenesis underscores the need for new studies. It appears that future large-scale projects should be preceded by smaller, shorter, less expensive biomarker-based studies that can serve as a link from mechanistic and observational research to human cancer prevention trials. These relatively inexpensive studies would provide human experimental evidence for the likely efficacy, optimum dose, and long-term safety of the intervention of interest that would then guide the design of safe, more definitive large-scale trials.
本次综述的目的是总结迄今已完成的、关于抗氧化剂作为癌症预防剂的最重要的人类临床试验，概述目前正在进行的研究，并讨论推进该领域研究所需的未来步骤。迄今为止，已有几项大型（至少有 7000 名参与者）试验测试了抗氧化补充剂预防癌症的功效。这些试验中测试的特定试剂（饮食来源的直接抗氧化剂和抗氧化酶的必需成分）包括β-胡萝卜素、维生素 E、维生素 C、硒、视黄醇、锌、核黄素和钼。没有一项已完成的试验提供令人信服的证据，证明使用传统的抗氧化相关维生素或矿物质进行癌症预防是合理的。我们对正在进行的试验的搜索确定了六个处于不同完成阶段的项目。其中五个试验使用硒作为干预物，单独或与其他试剂联合使用。迄今为止缺乏成功的原因可以用在下一代研究中需要考虑的各种因素来解释。这些因素包括选择特定感兴趣试剂的良好生物学依据的缺乏；迄今为止测试的试剂数量有限；使用药理学而非饮食剂量；以及干预和随访时间不足。后者强调需要替代终点，这些终点与增加的肿瘤发生风险相关（即风险标志物），但在肿瘤发生之前是可以检测到的。尽管膳食抗氧化剂是一大组多样化的化合物，但只有一小部分候选试剂已被测试。总之，将重点放在使用癌症发病率作为终点并测试相对有限数量的抗氧化剂的大型高预算研究上的策略在很大程度上是不成功的。以前的试验缺乏成功不应阻止我们通过调节氧化平衡来寻求预防癌症的新方法。相反，过度氧化应激与致癌作用之间的良好机制联系强调了开展新研究的必要性。似乎未来的大规模项目应该先进行较小、较短、成本较低的基于生物标志物的研究，这些研究可以作为从机制和观察性研究到人类癌症预防试验的联系。这些相对廉价的研究将为干预措施的可能疗效、最佳剂量和长期安全性提供人类实验证据，然后指导安全、更明确的大规模试验的设计。
