Cyclosporin A, but not everolimus, inhibits DNA repair in human fibroblasts and lymphoblasts

Abstract

Currently, approximately 4,800 organ transplantations are carried out per year and there are about 100,000 transplant patients in Germany who have an increased cancer risk, for example lymphomas, breast cancer and colon cancer. Furthermore, immunosuppressive medications can lead to the development of premalignant or malignant skin cancers. For example, cyclosporin A causes skin cancer in 40% of the transplant patients within 5 years after transplantation, and these include squamous cell carcinoma, basal cell carcinoma and cutaneous melanoma [Bouwes et al. 1996]. Azathioprine and steroids are associated with a moderately increased skin cancer risk but so far no increased skin cancer risk has been reported for sirolimus and everolimus [Euvrard et al. 2004]. It is generally believed that cyclosporin A, a calcineurin inhibitor, is involved in carcinogenesis is involved in carcinogenesis by promoting tumor growth and metastasis due to the suppressed immune system. In addition, it has been shown that cyclosporin A leads to upregulation of the tumor growth factor TGF[Hojo et al. 1999]. On the other hand, cyclosporin A may also affect tumor initiation, as this drug is associated with a decreased DNA repair capability in human keratinocytes [Yarosh et al. 2005]. Xeroderma pigmentosum (XP) patients have a defective nucleotide excision repair (NER) of UV-induced DNA damages and – like organ transplant patients – have an increased skin cancer risk in skin areas exposed to sunlight [Bootsma et al. 1998]. We assessed the influence of cyclosporin A in comparison to the mTOR inhibitor everolimus on the repair of UV-induced DNA damage in normal human fibroblasts and lymphoblasts.