Inflammation, oxidative DNA damage, and carcinogenesis.
Inflammation has long been associated with carcinogenesis, especially in the promotion phase. The mechanism of action of the potent inflammatory agent and skin promoter 12-tetradecanoyl phorbol-13-acetate (TPA) is unknown. It is thought that TPA selectively enhances the growth of initiated cells, and during this process, initiated cells progress to the preneoplastic state and eventually to the malignant phenotype. Many studies support the multistep nature of carcinogenesis, and a significant amount of evidence indicates that more than one genetic event is necessary for neoplastic transformation. Selective growth stimulation of initiated cells by TPA does not explain how further genetic events may occur by chronic exposure to this nongenotoxic agent. We and others have proposed that TPA may work, in part, by inciting inflammation and stimulating inflammatory cells to release powerful oxidants which then induce DNA damage in epidermal cells. Macrophages cocultured with target cells and TPA induce oxidized thymine bases in the target cells. This process is inhibited by both catalase and inhibitors of lipoxygenases, suggesting the involvement of both H2O2 and oxidized lipid products. Furthermore, macrophage populations that release both H2O2 and metabolites of arachidonic acid (AA) are more efficient at inducing oxidative DNA damage in surrounding cells than populations which only release H2O2 or metabolites of AA. In vivo studies demonstrated that SENCAR mice, which are sensitive to promotion by TPA, have a more intense inflammatory reaction in skin than C57LB/6 mice, which are resistant to promotion by TPA. In addition, macrophages from SENCAR mice release more H2O2 and metabolites of AA, and induce more oxidative DNA damage in cocultured cells than macrophages from C57LB/6 mice.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D004249:DNA Damage; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000150:complications*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D010084:Oxidation-Reduction; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D001095:Arachidonic Acids; D016718:Arachidonic Acid; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate