Effects of oral versus topical administration of cyclosporine on phorbol ester promotion of murine epidermal carcinogenesis

Abstract

In murine epidermal carcinogenesis, topical applications of cyclosporine (CsA), an immunosuppressant, have been reported to suppress 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. In the present study, we compared the effects of p.o. versus topical CsA on TPA promotion of mouse skin tumors and on TPA-induced epidermal hyperplasia. In the first series, groups of male Swiss Webster mice were initiated with 7,12-dimethylbenz(a)anthracene (200 nmol), and 3 days later they were placed on a basal diet or a diet containing 0.015% CsA. Then both groups of mice were promoted twice weekly with TPA (10 nmol) for 22 wk and observed for an additional 13 wk without TPA. No significant difference was observed in the incidence of skin papillomas between the 2 groups. By contrast, the incidences of squamous cell carcinomas in the mice maintained on CsA and basal diet were 67% and 28%, respectively. In the second series, the mice initiated with 200 nmol of 7,12-dimethylbenz(a)anthracene were treated twice weekly with 10 or 5 nmol of TPA for 24 wk. Ten to 15 min prior to each TPA application, one group received topical CsA in acetone (1 mg/mouse), and the other acetone. There was a significant inhibition of TPA promotion in the mice given topical CsA. Topical and p.o. CsA had no significant effect on epidermal hyperplasia induced by 4- to 8-wk treatment of TPA. The mice given topical CsA showed less inflammatory cell infiltrates in the dermis than the mice without CsA. The results indicate that the effect of CsA on TPA promotion of skin tumors depends on its routes of administration, and the p.o. administration enhances the progression of papillomas to squamous cell carcinomas.