Feig D I, Reid T M, Loeb L A
Joseph Gottstein Memorial Cancer Research Laboratory, Department of Biochemistry, University of Washington, Seattle 98195.
Cancer Res. 1994 Apr 1;54(7 Suppl):1890s-1894s.
In this review we will summarize recent data on reactive oxygen species-induced mutagenesis and consider its relationship to tumorigenesis in humans. With the use of a single-stranded DNA template it has been possible to correlate oxygen radical-induced chemical alterations at specific nucleotides with the types of mutations that occur when these altered bases are copied by DNA polymerases. This has allowed us to identify the types of mutations that occur secondary to a variety of oxidative stresses and study several of the mechanisms by which they arise. The most frequent mutations that result from reactive oxygen species-induced damage to DNA in bacteria are C to T transitions. These mutations, however, are not pathoneumonic for mutagenesis by oxygen-free radicals since they result from DNA damage caused by other genotoxic agents as well as by DNA polymerase errors. One type of mutation, a tandem CC to TT double substitution, has been shown to be induced by reactive oxygen species generated by a variety of systems and may be diagnostic for such damage. In studies with mammalian DNA polymerases, DNA damaged by reactive oxygen species yields mutations different from those observed in Escherichia coli. This diversity of mutagenic changes in these in vitro studies highlights the role of DNA replicating enzymes in specifying the types of mutations produced by reactive oxygen species. In conclusion, we will consider the role of reactive oxygen species in the pathogenesis of three common tumors, carcinoma of the liver, lung, and prostate with consideration on the possible use of antioxidant preventive therapy to slow tumorigenesis sufficiently to prevent clinical presentation of these cancers during the life span of a patient.
在本综述中，我们将总结关于活性氧诱导诱变的最新数据，并探讨其与人类肿瘤发生的关系。利用单链DNA模板，已能够将特定核苷酸处氧自由基诱导的化学改变与这些改变的碱基被DNA聚合酶复制时发生的突变类型联系起来。这使我们能够识别继发于各种氧化应激的突变类型，并研究它们产生的几种机制。细菌中活性氧诱导的DNA损伤导致的最常见突变是C到T的转换。然而，这些突变并非氧自由基诱变所特有，因为它们也可由其他基因毒性剂以及DNA聚合酶错误导致的DNA损伤引起。一种突变，即串联CC到TT双取代，已被证明可由多种系统产生的活性氧诱导，可能是这种损伤的诊断指标。在对哺乳动物DNA聚合酶的研究中，活性氧损伤的DNA产生的突变与在大肠杆菌中观察到的不同。这些体外研究中诱变变化的多样性突出了DNA复制酶在确定活性氧产生的突变类型中的作用。总之，我们将考虑活性氧在三种常见肿瘤（肝癌、肺癌和前列腺癌）发病机制中的作用，并探讨抗氧化预防性治疗是否有可能充分减缓肿瘤发生，从而在患者的寿命期间预防这些癌症的临床表现。
