Inhibitory potency of tacrolimus ointment on skin tumor induction in a mouse model of an initiation-promotion skin tumor

Abstract

Tacrolimus is a macrolide immunosuppressive agent, and tacrolimus ointment has been used as therapy for atopic dermatitis worldwide. Given that the immunosuppressive action of tacrolimus raises at least the theoretical potential for an increased risk of skin cancer, accurate assessment of the risk of developing skin cancer by tacrolimus ointment is necessary. The objective of the present study is to investigate the skin tumorigenic potential of commercially available tacrolimus ointment. We conducted a skin carcinogenicity study using an initiation-promotion (I/P) mouse model. Our study consisted of six groups (26 mice/group): sham control, absorptive ointment (AO), macrogol ointment (MO), tacrolimus ointment (TO) vehicle control, TO 0.03%, and TO 0.1%. Following a single administration of 7,12-dimethylbenz[α] anthracene (DMBA) to the dorsal skin of mice as an initiator, 12-O-tetra-decanoylphorbol-13-acetate (TPA) as a promoter and the test drugs were topically administered for 18 weeks. The incidence of skin hyperplasia in the TO 0.03% and TO 0.1% groups was reduced compared with both control groups (P < 0.05). Further, the incidence of skin neoplasia in the TO 0.03% (P < 0.05) and TO 0.1% groups (P < 0.01) was reduced in a dose-dependent manner compared with the sham control group. Tumor promotion effects on skin carcinogenesis were observed in the AO group, whereas inhibitory effects were observed in the MO group. TO 0.03% and TO 0.1% dose-dependently inhibit tumor induction in an I/P mouse model of skin tumors.