title: No acceleration of UV-induced skin carcinogenesis from evenly spread dietary intake of cyclosporine in contrast to oral bolus dosages.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: 1 Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands. 2 Department of Surgery, University of Regensburg, Regensburg, Germany. 3 Address correspondence to: Dr. Frank R. de Gruijl, Department of Dermatology, Leiden University Medical Center (LUMC), Postal Zone S2P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors: Pieter
authors: P
authors: Voskamp
authors: Carolien A
authors: CA
authors: Bodmann
authors: Gudrun E
authors: GE
authors: Koehl
authors: Cornelis P
authors: CP
authors: Tensen
authors: Jan Nico Bouwes
authors: JN
authors: Bavinck
authors: Rein
authors: R
authors: Willemze
authors: Edward K
authors: EK
authors: Geissler
authors: Frank R
authors: FR
authors: de Gruijl
mesh_terms: D000284:Administration, Oral; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D016572:Cyclosporine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D051379:Mice; D008812:Mice, Hairless; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000209:etiology; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy* / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine