Introduction

Oxygen free radicals and other reactive oxygen species (ROS) are generated in living cells as (a) by product of normal metabolism, (b) physiological signaling molecules, and (c) inflammatory responses to eliminate invading pathogenic microorganisms or by exogenous sources such as environmental

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agents and ionizing radiation.1'2 It is now increasingly evident that free radicals are involved in the pathogenesis of several diseases, including cancer. A substantial body of work implicates free-radical-induced DNA damage as the cause of mutagenesis that drives carcinogenesis.3-6

In the development of cancer, an accepted paradigm is the multistep model of carcinogenesis in mouse skin. According to this model, three steps—initiation, promotion, and progression—are involved in the cancer development7. Free radicals play an important role in the induction of the first two steps. Initiation, which involves mutations and alterations in nucleic acids, is caused by free-radical attack. A majority of carcinogenic agents that are regarded as initiators produce free radicals that cause mutations, strand breaks, and sister chromatid exchange in DNA. Promotion involves the selective clonal proliferation of the initiated cells.8 Promoters are compounds that stimulate formation of free radicals and modify the antioxidant defense system. Progression, the final stage, involves irreversible malignant transformation from preneoplastic lesions.9

Free radicals act in numerous other ways to promote carcinogenesis. Apart from DNA damage, radicals can oxidatively damage lipids and proteins.1011 While unrepaired DNA damage can be mutagenic and can cause uncontrolled cell growth, damage to lipids and proteins modifies membrane structure and function, cell-cell communication, and activity of enzymes, resulting in modulation of cell proliferation and growth.12

Free radicals are now known to regulate signal-transduction processes involved in cell differentiation, survival, and transformation.13 These signaling processes can activate a number of early-response genes that are involved in tumor promotion. Thus at the cellular level, the free-radical-induced damage, termed as "oxidative stress," causes changes in gene expression, signal transduction, and posttranscriptional and posttranslational modifications that regulate cell growth and differentiation. The cumulative oxidative damage has thus been implicated in participation in cancer.1415

In this chapter we discuss the free-radical-induced modification of the various cellular components and the mechanisms by which oxidative stress leads to carcinogenesis. The role of signaling pathways in regulating cell proliferation and in promoting carcinogenesis is also discussed.

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