Reactive oxygen species in tumorigenesis.
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.
Feig
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Joseph Gottstein Memorial Cancer Research Laboratory, Department of Biochemistry, University of Washington, Seattle 98195.
Reid
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Loeb
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D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D008322:Mammals; D016296:Mutagenesis; D010100:Oxygen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000473:pathology
D002273:Carcinogens; D010100:Oxygen