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Loss of these functions results in genomic instability and increased cancer risk.Given the importance of DNA repair pathways in cancer prevention, it is reasonable to speculate that disruption of these pathways by exogenous agents could contribute to carcinogenesis as well.Such an agent would be expected to act as a cocarcinogen, and enhance the mutagenic and carcinogenic activity of genotoxic carcinogens.A possible example of this type of cocarcinogen is arsenic. Epidemiological studies show that arsenic exposure is strongly associated with the development of skin lesions, including skin cancers. Elevated risk of other malignancies, such as bladder, lung, kidney, and liver carcinomas, is also associated with arsenic exposure.Tests of the mutagenic activity of arsenic in a variety of assay systems have generally been negative. However, in cell culture systems, arsenic has been shown to enhance the mutagenic activity of other carcinogenic agents.This enhancement of mutagenesis was shown to be associated with a suppression of DNA repair. Recently, arsenic was shown to act as a cocarcinogen with UV radiation in the induction of skin tumors in the hairless mouse. These results suggest that the carcinogenic activity of arsenic may be due in part to its ability to suppress DNA repair pathways.However, it is not clear whether genetic instability is a prerequisite for cancer development or whether it is a consequence of the cancer phenotype.Certainly, as discussed above, defects in cell cycle checkpoints and DNA repair pathways that increase genetic instability also increase cancer risk.Even conring in a single cell is sidering that there are perhaps cells in the body and perhaps cell divisions during the average life span, this. Since cancer is leads to a calculated cancer risk of much more prevalent than that, this suggests that an essential step in cancer development is an increase in mutation frequency.This increase could be due to an inhibition of any of the pathways that normally serve to maintain genomic stability.Whether disruption of normal mutationavoidance pathways is also responsible for such genomic instability remains to be demonstrated.Although it is clear that an increase in mutagenesis can promote cancer development, it K.Thus, the counter argument invokes proliferation and selection of mutant cells.If the rst   hit provides a growth advantage to the cell, this cell will proliferate, increasing the probability of a second hit within the expanded population.Either argument is consistent with the observed increase in cancer incidence with age a longer time and more cell divisions increase the probability of generating the mutator state or allowing for rounds of mutagenesis and clonal expansion.It has been postulated that stimulation of cell proliferation by tumor promoters, natural hormones, or as a result of cell injury can enhance the mutagenic effects of endogenous or exogenous genotoxic agents. A wide variety of nonmutagenic agents that stimulate cell proliferation can increase cancer risk, perhaps through the enhancement of mutagenesis.The link between cell proliferation and mutagenesis has been demonstrated in mouse model systems.It is possible that cell turnover caused by chronic infections, proliferation of target tissues induced by hormones, such as estrogen, or <a href="http://www.targetmol.com/compound/Chloramphenicol">Targetmol's Chloramphenicol</a> hyperplasia due to exposure to environmental agents, such as arsenic, may all enhance mutagenesis.

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