Scheduled and unscheduled DNA synthesis in epidermal cells of hairless mice treated with immunosuppressive drugs and UVB-UVA irradiation

Abstract

The effects of the immunosuppressive drugs azathioprine, prednisolone and cyclosporin A, and UV irradiation on scheduled DNA synthesis, representing mitotic activity, and unscheduled DNA synthesis, representing DNA repair activity, in the skin of hairless mice were determined autoradiographically following intradermal administration of [3H]-thymidine. Azathioprine and prednisolone, and, to a lesser extent, cyclosporin A, were found to impair normal repair of UVR-induced DNA lesions in epidermal keratinocytes. Prednisolone, but not the other two drugs, further suppressed the normal delayed mitotic response in the skin following UVR. The depressive effects of these drugs, particularly the combined azathioprine/prednisolone regime, on scheduled and unscheduled DNA synthesis are considered likely to predispose skin to mutagenic and carcinogenic processes.

Molecular and Immunologic Mechanisms of Cancer Pathogenesis in Solid Organ Transplant Recipients

“…However, it was subsequently shown that Azathioprine (Aza) and CS could lower the repair of DNA lesions induced by solar UV radiation (17,18). CS Figure 2).…”

Cancer incidence and risk factors after solid organ transplantation

“…9,56,59,65 Independent of their immunosuppressive effects, there is laboratory evidence that azathioprine and cyclosporine have direct biological effects capable of enhancing UVR-related carcinogenesis. Azathioprine sensitizes DNA to ultraviolet A radiation, 66 reducing the minimal erythema dose in skin cells of treated patients, 67,68 while cyclosporine inhibits DNA repair and apoptosis in ultraviolet B radiation-exposed human keratinocytes. 69,70 However, exposure to either of these agents has not been consistently associated with an increased risk of NMSC.…”

p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomarivus status

“…A number of European studies report a 27 ± 40% cumulative risk of developing either a basal cell (BCC) or squamous cell cancer (SCC) within the ®rst 20 years following transplantation (Hartevelte et al, 1990;London et al, 1995;McGregor and Proby, 1995). Several mechanisms have been suggested to account for this increase, including chemical carcinogenesis (Lennard et al, 1985;Swann et al, 1996), altered DNA repair (Kelly et al, 1987;Swann et al, 1996) and loss of immune surveillance (Doll and Kinlen, 19970). Human papillomaviruses (HPV) have also been implicated, since other tumours which occur at high frequency in transplant recipients are those associated with a viral aetiology (Morris et al, 1996), including lymphoma, Kaposi's sarcoma and anogential SCC (Birkeland et al, 1995).…”

“…Such mutations are very rarely observed in sporadic NMSC and the signi®cance of these mutations in the context of post-translant skin cancer is not clear. However, recent suggestions that chronic exposure to azathioprine, and perhaps also to other immunosuppressive drugs used in transplantation, may contribute to carcinogenesis by selecting for clones defective in post-replicative DNA repair requires further study (Kelly et al, 1987;Swann et al, 1996).…”