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 cyclosporin A (CsA) has been reported. The relationship between the pathogenesis of skin carcinogenesis and the dose of CsA is still unclear.


OBJECTIVE
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.


CONCLUSIONS
These data suggest that oral administration of CsA in excess of a certain dose can accelerate tumour development in mice.
Yajima
Y
Y
Department of Dermatology, Showa University School of Medicine, Tokyo, Japan.
Sueki
H
H
Oguro
T
T
Yoshida
T
T
Iijima
M
M
D015127:9,10-Dimethyl-1,2-benzanthracene; D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D008812:Mice, Hairless; D009367:Neoplasm Staging; D010212:Papilloma / Q000139:chemically induced* / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate
D002273:Carcinogens; D007166:Immunosuppressive Agents; D015127:9,10-Dimethyl-1,2-benzanthracene; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate