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Key Words cancer, reactive oxygen species, oxidative DNA damage, apoptosis, cell proliferation, gene expression, signal transduction
Abstract Chemical carcinogenesis follows a multistep process involving both mutation and increased cell proliferation. Oxidative stress can occur through overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Important to carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation (induced by oxidant-induced DNA damage), as well as modification of gene expression. In particular, signal transduction pathways, including AP-1 and NFκB, are known to be activated by reactive oxygen species, and they lead to the transcription of genes involved in cell growth regulatory pathways. This review examines the evidence of cellular oxidants' involvement in the carcinogenesis process, and focuses on the mechanisms for production, cellular damage produced, and the role of signaling cascades by reactive oxygen species.
OVERVIEW
Chemically induced neoplasia is a multistep process involving DNA damage and cell proliferation. Chemical carcinogens impact on various stages of this process and function through modification of cellular and molecular events. Investigators recognizing the apparent differences by which chemicals participate in the carcinogenesis process, proposed the use of the descriptors, "genotoxic" and "epigenetic" (nongenotoxic), to help further refine the mechanisms by which a carcinogen was functioning (1). Genotoxic agents usually refer to chemicals that directly damage genomic DNA, which in turn can result in mutation and/or clastogenic changes. Chemicals in this category are frequently activated in the target cell and produce a dose-dependent increase in neoplasm formation. A second category of carcinogenic compounds (nongenotoxic) appear to function through non-DNA reactive or indirect DNA reactive mechanisms. Although much less is known about the exact mode of action of nongenotoxic carcinogens, they modulate cell growth and cell death. Changes in gene expression and cell growth parameters are paramount in the action of nongenotoxic carcinogens. These agents frequently function during the promotion stage of the cancer process (2,3).
The induction of neoplasia in rodents by chemical and physical agents involves a multistage process. At least three distinct stages of the carcinogenesis process have been defined (2). These include initiation, promotion, and progression (Figure 1). Initiation involves the formation of a mutated, preneoplastic cell from a genotoxic event. The formation of the preneoplastic, initiated cell...