Enhancement by adriamycin of the effects of 12-O-tetradecanoylphorbol-13-acetate on mouse epidermal glutathione peroxidase activity, ornithine decarboxylase induction and skin tumor promotion.
Adriamycin (ADR) failed to inhibit and paradoxically enhanced the biological action of 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis in vivo and in vitro. In the presence of ADR, the tumor promoter caused a greater sequential rapid increase and prolonged decrease in glutathione (GSH) peroxidase (GSH:H2O2 oxidoreductase, EC 1.11.1.9) activity accompanied by a greater decrease in the ratio of reduced (GSH)/oxidized (GSSG) glutathione in isolated epidermal cells. The ability of ADR to deplete the intracellular level of GSH correlated with its ability to increase basal and TPA-induced ornithine decarboxylase (ODC, L-ornithine carboxylase, EC 4.1.1.17) activities. In vivo, topical ADR treatments also enhanced TPA-induced ODC activity as well as the tumor-promoting ability of TPA in the two-stage system of mouse skin carcinogenesis. Since lipid peroxidation has been associated with ADR toxicity, these data suggest that the enhancement of the tumor-promoting ability of TPA by ADR may be the result of an increased oxidative challenge that overwhelms the GSH-dependent antioxidant protective system of the epidermal cells.
D000287:Administration, Topical; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D004790:Enzyme Induction; D004817:Epidermis / Q000201:enzymology; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D005979:Glutathione Peroxidase / Q000378:metabolism*; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D010704:Phorbols / Q000494:pharmacology*; D012867:Skin / Q000201:enzymology*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D010704:Phorbols; D004317:Doxorubicin; D005979:Glutathione Peroxidase; D009955:Ornithine Decarboxylase; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate; D019803:Glutathione Disulfide