Free oxygen radicals: necessary contributors to tumor promotion and cocarcinogenesis

The two stage model of carcinogenesis postulates that agents which lead to tumor formation are either initiating or promoting agents. Initiating agents induce chemical modifications of DNA. Promoting agents have been assumed to induce cell proliferation and thereby establish a milieu in which the initiated cells can express their irreversibly altered genotype. Promoters can induce both the migration of leukocytes to the skin and stimulate their respiratory activity leading to the formation of active O2 species which cause lipid peroxidation and thereby change membrane properties. However, it was recently found that the O2 species emanating from promoter-activated leukocytes also cause formation of strand breaks both in the DNA of the leukocytes themselves and in the DNA of cells cocultivated with such leukocytes. The contribution of activated O2 species to tumor promotion has been confirmed by the finding that antioxidants and copper containing superoxide dismutase (SOD)-mimetic compounds, protease inhibitors and retinoids (which block free radical formation) inhibit promotion. Furthermore, cocarcinogens such as gossypol and pyrogallol may also cause conversion of O2 to the superoxide anion radical. The heritable change caused by initiators may render the cell more vulnerable to promoter-mediated DNA damage. Experimental investigation of these hypotheses may elucidate our understanding of the contribution of promoter-mediated DNA damage in tumorigenesis and identify preventive agents for carcinogenesis.