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Active oxygen species have long been known to be mutagenic,
hence playing a role in cancer formation.
Role of Oxidative DNA damage in initiation:
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
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.
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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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