Redox Modulation of Chemotherapy-Induced Tumor Cell Killing and Normal Tissue Toxicity

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Abstract
The traditional view of intracellular oxidation–reduction, or redox, balance in epithelial cells, which is more than three decades old ( 1 ) , emphasizes a dynamic equilibrium between the production of reactive oxygen species (ROS; these include superoxide anion, O 2− ; hydrogen peroxide, H 2 O 2 ; and chemical species with the characteristics of the hydroxyl radical, • OH) by a variety of flavin dehydrogenases that occupy essentially every cellular compartment, and the detoxification of these species by a broad range of antioxidant enzymes and related small molecules ( 2 ) . ROS are produced by the mitochondrial electron transport chain during the course of cellular respiration, by cytochrome P450–related components of microsomes ( 3 ) , and, in many human tumors, by the recently described family of membrane-bound NADPH oxidases that possess a high degree of homology with components of the NADPH oxidase system of polymorphonuclear leukocytes and macrophages ( 4 ) . ROS are detoxified by a complex and interactive series of proteins and small molecules—including members of the superoxide dismutase, glutathione peroxidase, and peroxiredoxin gene families, as well as catalase—that ultimately reduce O 2− and H 2 O 2 (or lipid peroxides) to nontoxic species, such as lipid alcohols or water ( 5 , 6 ) .