Effects of oral administration of ciclosporin A on skin carcinogenesis: a study using the two-stage carcinogenesis protocol in mice

Background. Development of malignant skin neoplasms in patients receiving ciclosporin A (CsA) has been reported. The relationship between the pathogenesis of skin carcinogenesis and the dose of CsA is still unclear. Aim. To clarify the effect of oral administration of CsA, especially its dose, on skin carcinogenesis. Methods. Hr-1 hairless mice were assigned to the following four groups: (i) control group (n = 8), given vehicle intragastrically six times/week and acetone applied to the skin of the back; (ii) chemical-alone (n = 11), given vehicle intragastrically + application of 7,12-dimethylbenz[a]anthracene (DMBA) once week and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) twice week to the back; (iii) CsA-alone group (n = 8), given CsA intragastrically (10 mg/kg) six times/week and vehicle applied to the back twice week; and (iv) CsA + chemical group (n = 8), given 10 mg/kg CsA intragastrically + topical DMBA and TPA. The number of papules > 3 mm in diameter that had developed on the back after 15 weeks was counted. The mean epidermal thickness and number of dermal infiltrates were determined. The same experiments were performed using CsA at doses of 5 and 20 mg/kg. Results. Oral administration of either 10 or 20 mg/kg CsA significantly enhanced the formation of papillomas by DMBA and TPA, but no enhancement was observed when 5 mg/kg CsA was administered. The mean epidermal thickness and number of dermal infiltrates were significantly greater in the CsA + chemical group than in the chemical-alone group. Conclusion. These data suggest that oral administration of CsA in excess of a certain dose can accelerate tumour development in mice.