title: Skin cancer in organ transplant recipients: effects of immunosuppressive medications on DNA repair.
abstract: UV-induced skin cancers comprise a major problem in organ transplant recipients (OTRs). Cyclosporin A, a calcineurin inhibitor, is used as a standard immunosuppressant and clearly increases the skin cancer risk. Azathioprine does not appear to result in such an increase in skin cancer risk, and mTOR inhibitors are associated with an even lesser skin cancer risk. The underlying molecular mechanisms of these clinically important differences among immunosuppressants are still unclear and may relate to other than immunological effects. Insights may be gained by the multistep skin cancer theory and xeroderma pigmentosum, where defective nucleotide excision repair (NER) results in a cellular mutator phenotype and cutaneous carcinogenesis. This viewpoint assay summarizes current knowledge about the influence of the most commonly used immunosuppressive drugs in OTRs on DNA repair. Calcineurin inhibition results in a 200-fold increased skin cancer risk compared with the normal population and inhibits NER. The skin cancer risk under azathioprine is threefold less compared with calcineurin inhibitors, which may relate to inhibition of only the last step of NER, i.e. gap filling. mTOR inhibitors do not reduce NER in the global genome and can inhibit the growth of already initiated tumors, which may account for the markedly reduced skin cancer risk compared with calcineurin inhibitors. We conclude that OTRs may benefit from treatment regimens other than calcineurin inhibitors and speculate that a targeted modulation of calcineurin-dependent signalling may prevent UV-induced tumor formation by enhancing NER not only in OTRs but also in the general population, at least in part.
authors.affiliation: Department of Dermatology, Venerology, and Allergology, Georg-August-University, Goettingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Kuschal
authors.forename: Kai-Martin
authors.initials: KM
authors.lastname: Thoms
authors.forename: Steffen
authors.initials: S
authors.lastname: Schubert
authors.forename: Annika
authors.initials: A
authors.lastname: Schäfer
authors.forename: Lars
authors.initials: L
authors.lastname: Boeckmann
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schön
authors.forename: Steffen
authors.initials: S
authors.lastname: Emmert
mesh_terms: D065095:Calcineurin Inhibitors; D004260:DNA Repair; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016377:Organ Transplantation; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000276:immunology / Q000517:prevention & control; D014983:Xeroderma Pigmentosum / Q000150:complications
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents