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Sunday June 16, 2002 10:25 PM GMT
Active oxygen species have long been known to be mutagenic, hence playing a role in cancer formation.
Role of Oxidative DNA damage in initiation:
For the initiation of carcinogenesis, a permanent genetic alteration that will be passed on to the progeny of the initiated cell must occur. DNA modification must be sufficiently tenacious to escape efficient repair processes but not so extensive that cell death results. Many of the genetic lesions induced by oxidants will be toxic; however, deletion or rearrangement of promoter and enhancer areas can mediate gene deregulation most probably in the form of inactivation. Allelic deletion can also occur through oxidative mechanisms. Hence, the damage produced by oxidative mechanisms could result in the inactivation/loss of certain tumour suppressor genes, which would lead to the initiation or progression of carcinogenesis. Inactivation of tumour suppressor genes can also result from the alteration of a single base pair. This is called point mutation. Detailed analysis of point mutations due to oxidant exposure by the laboratories of Halliwell and Dizdaroglu has shown that under biologically relevant exposure conditions to oxidants, a predominance of G and C modifications are produced (Aruoma, Halliwell and Dizdaroglu; 1989).
The importance of G-C sites as targets of oxidative DNA damage:
A common site for point mutations in both the p53 and retinoblastoma tumour suppressor genes is the G-C base pairs. Similarly, normal cellular genes can be converted into oncogenes through a single base pair change. Again, G-C pairs provide a common target for activating point mutations. For e.g. the most frequent mutations in the ras family of oncogenes are the G-C base pairs in codons 12 and 13. Hence both oncogenes and tumour suppressor genes represent vulnerable targets for mutation by oxidative stress. The propensity of oxidative stress to induce mutations at G-C sites that persist following replication and repair has been demonstrated in mutation reporter plasmid system by Moraes et al.(Moraes et al. 1989). Other agents whose DNA-damaging actions are thought to be mediated by active oxygen species also produce the same pattern of DNA damage. Single base substitution is the most common lesion with G-C base pairs the predominant substitution target (Miles et al. 1989). The prevalence of mutations at G-C base pairs in the DNA has not been reported in all model systems. Some studies revealed a predominance of lesions at A and T sites (Moraes et al. 1989). In these studies however, spontaneous mutation of the plasmid occurred primarily at G-C sites. The oxidised products of A and T bases are not without consequence; a Salmonella tester strain with A-T base pairs at the site of mutation was sensitive to a variety of oxidative mutagens (Levin et al. 1982). While mutagenic lesions at G-C appear to predominate in model systems approximating in vivo exposure to oxidative stress, manipulation of the treatment conditions can activate other mechanisms of mutation.
Role of transition metals in oxidative DNA damage:
The addition of exogenous metals to DNA in solution can promote the generation of reactive oxygen species that can damage bases in DNA. In vitro it has been shown that the addition of copper produces more mutations than the addition of iron (Guyton and Kensler, 1993). At the same time DNA shows high specificity for the binding of copper as compared to other metal ions. The binding of copper to DNA is a natural occurrence. This binding has several important physiological functions. Of the many functions it has, it is known to cause stabilization of the scaffolding structure of DNA when the histones are dissociated, during both the transcriptional and DNA synthesis phase in metaphase. It may also act as a linker between DNA and associated nuclear proteins.
Copper can interact directly with DNA bases and a large body of evidence suggests that this copper is specifically bound to DNA at G-C base pair sites (Guyton and Kensler, 1993).
Hence while the binding of copper is necessary for the stabilization of DNA, the bound copper may provide an advantageous site for the deleterious reactions of reactive oxygen species. In particular, in the presence of copper redox cycling of electrons results in the formation of the highly reactive hydroxyl radical from the less reactive superoxide and hydrogen peroxide.
The role of free radicals in tumour promotion:
Substantial evidence has it that there is a role for oxidative stress in the later stages of carcinogenesis (Cerutti P, 1985). However much of the evidence is indirect. For example many antioxidants and oxidant detoxifiers have been shown to decrease a wide diversity of promotion related biochemical processes. Other evidence is suggested by the fact that tumour promoters have been found to create an environment of oxidative stress. Promoters provide sudden and sustained decrease in cellular antioxidant defences, including superoxide dismutase, catalase and glutathione peroxidase activities.
Tumour promotion in vivo is comprised of a series of complex molecular events (Guyton and Kensler, 1993). In tumour promotion the initiated cell population is stimulated to expand while the normal population is not. This can occur by providing a growth stimulus to the initiated cells or as the indirect result of the effects of the promoter on the normal population. By selectively stimulating terminal differentiation to the normal cells tumour promoters can induce proliferation where the initiated cells proliferate to fill the void left by the removal of their normal counterparts. The phorbol ester promoters have been demonstrated to stimulate initiated cells both directly and indirectly. Oxidative stress may similarly be able to provide this type of dual signal. The initiation process may confer one or more phenotypic changes.
The role of free radicals in malignant conversion:
By selectively modifying gene expression in initiated cells, tumour promoters can elicit the production of clonally-derived benign growths. These tumours can be converted into rapidly growing malignant neoplasms through further DNA damage. Experimentally treating papillomas with either an initiator or a free radical-generating agent that can elicit DNA damage, such as benzoyl peroxide could produce cancers from benign tumours. This may result in further direct DNA base modification or the transposition of genetic material. A second, heritable genetic lesion is thus produced in one or more cells in the benign tumour, leading to irreversible transformation into an autonomously growing cancer (Guyton and Kensler, 1993).
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