RESUMO
Immunosuppressive medication in renal transplant recipients (RTR) strongly increases the risk of cancers on sun-exposed skin. This increased risk was considered an inevitable collateral effect of immunosuppression, because UV-induced carcinomas in mice were found to be highly antigenic. Here, we posed the question whether immunosuppression also increases the frequency of p53-mutant foci ('p53 patches'), putative microscopic precursors of squamous cell carcinomas. As the majority of RTR was kept on azathioprine for most of the time, we investigated whether this drug could increase UV-induced p53 patches by immunosuppression. As azathioprine can impair UV-damaged DNA repair under certain conditions, we also investigated whether DNA repair was affected. Archive material of RTR and immunocompetent patients (ICP), as well as azathioprine-administered hairless mice were examined for p53 patches. DNA repair was investigated by ascertaining the effect of azathioprine on unscheduled DNA synthesis (UDS) in UV-irradiated human keratinocytes. P53 patches were more prevalent in RTR than in ICP in normal skin adjacent to carcinomas (P = 0.02), in spite of a lower mean age in the RTR (52 vs 63 years, P = 0.001), but we found no increase in UV-induced p53 patches in mice that were immunosuppressed by azathioprine. We found a significant reduction in DNA repair activity in keratinocytes treated with azathioprine (P = 0.011). UV-induced UDS in humans is dominated by repair of cyclobutane pyrimidine dimers, and these DNA lesions can lead to 'UV-signature' mutations in the P53 gene, giving rise to p53 patches.
Assuntos
Azatioprina/efeitos adversos , Carcinoma de Células Escamosas/genética , Reparo do DNA/efeitos dos fármacos , Epiderme/metabolismo , Genes p53 , Imunossupressores/efeitos adversos , Neoplasias Cutâneas/genética , Adulto , Idoso , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Transformação Celular Neoplásica/genética , Células Clonais/metabolismo , Epiderme/efeitos da radiação , Feminino , Humanos , Imunocompetência/genética , Hospedeiro Imunocomprometido/genética , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Transplante de Rim , Masculino , Camundongos , Camundongos Pelados , Pessoa de Meia-Idade , Mutação , Neoplasias Cutâneas/induzido quimicamente , Raios Ultravioleta/efeitos adversosRESUMO
A randomized-controlled trial with paired observations was performed with 40 organ-transplant recipients to assess the preventive effect of photodynamic therapy (PDT) on the development of new squamous-cell carcinomas and to evaluate the effect of PDT on the number of keratotic skin lesions. The treatment area consisted of a randomly assigned forearm and the corresponding hand, whereas the other forearm and hand served as the control area. After the initial visit, follow-up visits were scheduled at 3-monthly intervals during 2 years. No statistically significant difference was found in the occurrence of new squamous-cell carcinomas between the treated and untreated arms: after 2 years of follow-up, we observed 15 squamous-cell carcinomas in nine out of 40 PDT-treated arms and 10 squamous-cell carcinomas in nine out of 40 control arms. The number of keratotic skin lesions increased in both arms, but was less pronounced in the PDT-treated arm. After 1 year of follow-up, a trend in favor of the PDT-treated arm was observed, but statistical significance was not reached. Nearly 80% of the patients reported mild to severe adverse effects consisting of pain and a burning sensation, immediately after the treatment. No long-term adverse events were noted. In conclusion, PDT does not appear to prevent the occurrence of new squamous-cell carcinomas in organ-transplant recipients, but to some degree, reduces the increase of keratotic skin lesions.
