No Acceleration of UV-Induced Skin Carcinogenesis from Evenly Spread Dietary Intake of Cyclosporine in Contrast to Oral Bolus Dosages

Abstract

Organ transplant recipients using the immunosuppressant cyclosporine have an increased risk for developing nonmelanoma skin cancer. Disparate effects of cyclosporine have, however, been reported on UV-induced skin carcinogenesis in mouse experiments. Therefore, we set out to compare three experimental protocols using mice, with the aim to emulate most closely the increased skin cancer risk in organ transplant recipients. UV carcinogenesis was performed in hairless SKH-1 mice by three protocols: dietary cyclosporine and daily UV exposures, dietary cyclosporine after a period of UV exposures, and bolus dosing cyclosporine by gavage and repeated UV exposures. Using chronic UV exposure, continuous dietary administration of cyclosporine was shown to inhibit tumor formation. Dietary cyclosporine after a period of UV exposures did not affect ensuing UV carcinogenesis. However, in contrast with dietary cyclosporine, bolus dosages of cyclosporine by gavage, resulting in strongly varying blood levels of cyclosporine, increased tumor development in chronically UV-exposed mice. There was no difference in tumor development between mice UV-irradiated during peak or trough levels of cyclosporine in the blood. Time-averaged levels in these mice were similar to those with cyclosporine in the diet. Cyclosporine in bolus doses appears to increase skin cancer development, whereas cyclosporine administration more evenly spread over time does not. Extrapolation to transplant patients suggests that the mode of administrating cyclosporine may be crucial for the increased skin cancer risk and that this risk might be lowered with a more steady release of cyclosporine in the body.