Anti-tumor-promoting action of FK506, a potent immunosuppressive agent

The effect of FK506, a potent immunosuppressive agent, on 7,12-dimethylbenz[a]anthracene-initiatedand 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skinpapilloma formation was examined in CD-1 mice. A topical applicationof FK506 to mouse skin 15 min before each TPA treatment resultedin a dose-related inhibition of tumor formation. FK506 (1 µmol)almost completely inhibited tumor formation. This inhibitoryeffect of FK506 was not due to any damage inflicted on the initiatedcells but due to its antitumor-promoting action. A topical applicationof FK506 also inhibited epidermal ornithine decarboxylase inductionand skin inflammation caused by TPA in a dose-related manner.Significant inhibition by FK506 of TPA-induced endogenous proteinphosphorylation in intact epidermal cells was not detected.These results indicate that FK506 inhibits TPA-induced tumorpromotion at a step distal to the endogenous protein phosphorylationby TPA.