Expression of Oxidant Stress-Related Genes in Tumor Promotion of Mouse Epidermal Cells JB6

The evidence is convincing that oxidants and agents which induce a cellular prooxidant state can act as carcinogens, in particular as promoters and progressors (1–7). Bonafide oxidants with promotional activity include H₂O₂, superoxide, ozone, hyperbaric oxygen, peroxyacetic acid, chlorobenzoic acid, benzoyl-peroxide, decanoylperoxide, cumene-hydroperoxide, p-nitro-perbenzoic acid and periodate (8,9). Infiltrated phagocytes represent a major source of oxidants in inflamed tissues (10,11) and in several instances inflammation appears to be a prerequisite for promotion (12–14). Tumor promotion results in the clonal expansion of Initiated cells at the cost of the surrounding tissue. This can involve the modulation of the expression of growth- and differentiation-related genes and selective cytostatic effects on non-initiated cells. It is of obvious interest to elucidate the mechanism(s) by which oxidants exert their promotional activity. In addition, the question arises whether other classes of promoters which lack oxidizing properties might owe at least part of their promotional activity to the induction of a cellular prooxidant state (1). Support for this notion has been obtained for the phorbol-ester promoter phorbol-12-myristate-13-acetate (PMA). PMA induced an increase in the ratio of oxidized over reduced glutathione in mouse epidermal cells (5). Furthermore, several antioxidants, in particular CuZn-superoxide dismutase (SOD), inhibit cellular reactions induced by PMA as well as promotion invivo and invitro implicating the superoxide radical O₂ in its mechanism of action (1, 4, 9, 15).