Molecular effects of cyclosporine and oncogenesis: a new model

André, Nayara Delgado

doi:10.1016/s0306-9877(04)00242-7

Cited by 8 publications

(10 citation statements)

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“…Topical calcineurin inhibitors have also been successful for diseases such as atopic dermatitis because their steroid-sparring effect minimizes dermal atrophy, striae, and telangiectasia, and they were considered as preventing the skin cancer risk. But, evidence is accumulating that systemic immune suppression is not the only cause of the increased risk of skin cancer (André et al, 2004), and at least in the case of renal transplant patients, their DNA repair capacity is impaired (Vamvakas et al, 1996;Herman et al, 2001). We report here that the calcineurin inhibitors CsA and ascomycin each inhibited repair of UV-induced DNA damage in human keratinocytes, the target cell for most skin cancers.…”

Section: Discussionmentioning

confidence: 52%

Calcineurin Inhibitors Decrease DNA Repair and Apoptosis in Human Keratinocytes Following Ultraviolet B Irradiation

Yarosh

Peña

Nay

et al. 2005

Journal of Investigative Dermatology

182

139

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The use of calcineurin inhibitors in solid organ transplantation results in an increased risk of skin cancer. We examined the effect of these drugs on DNA repair in normal human keratinocytes after ultraviolet B (UVB) irradiation. We found that both cyclosporine A (CsA) and ascomycin inhibited removal of cyclobutane pyrimidine dimers, and that they also inhibited UVB-induced apoptosis. We also observed that UVB induced nuclear localization of the transcription factor nuclear factor of activated T-cells (NFAT), and that this was blocked by CsA and ascomycin. These data suggest that the increased risk of skin cancer observed in organ-transplant patients may be as a result of not only systemic immune suppression but also the local inhibition of DNA repair and apoptosis in skin by calcineurin inhibitors. These findings may have implications for the use of topical calcineurin inhibitors in sun-exposed skin and eyes.

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Section: Discussionmentioning

confidence: 52%

Calcineurin Inhibitors Decrease DNA Repair and Apoptosis in Human Keratinocytes Following Ultraviolet B Irradiation

Yarosh

Peña

Nay

et al. 2005

Journal of Investigative Dermatology

182

139

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“…Cyclosporin A indeed impairs DNA repair 25 and lymphocyte apoptosis, 26 while increasing IL-6 production by EBV-infected B cells. 27,28 These effects promote lymphocyte immortalization and could therefore explain the increased incidence of PTLD observed after cyclosporin A 29 and tacrolimus 30,31 introduction.…”

Section: Discussionmentioning

confidence: 98%

Maintaining calcineurin inhibition after the diagnosis of post-transplant lymphoproliferative disorder improves renal graft survival

Serre¹,

Michonneau²,

Bachy³

et al. 2014

Kidney International

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Post-transplant lymphoproliferative disorder (PTLD) is an uncontrolled proliferation of transformed lymphocytes fostered by immunosuppression. In addition to chemotherapy, treatment of PTLD includes a reduction of maintenance immunosuppression. Patients with PTLD have an increased risk of graft loss, suggesting that reduced immunosuppression strategy needs to be optimized with regard to graft outcome. Here we retrospectively reviewed 101 cases involving PTLD to identify the risks associated with graft loss. During a median follow-up of 70 months, 39 patients died and 21 lost their graft. Multivariate analysis found that an eGFR under 30 ml/min per 1.73 m(2) at PTLD diagnosis, a biopsy-proven acute rejection episode following reduction of immunosuppression, and the absence of calcineurin inhibition in maintenance immunosuppression are independent risk factors for allograft loss. Neither the type of PTLD nor the chemotherapy regimen was predictive of allograft failure. Histological analysis of graft biopsies showed that maintaining calcineurin inhibition after the diagnosis of PTLD reduced the risk of developing de novo anti-HLA antibodies and humoral rejection. Remarkably, calcineurin inhibitor maintenance was neither associated with higher mortality nor with worse progression-free survival. Thus, maintaining calcineurin inhibition at a reduced dose after the diagnosis of PTLD seems safe and may improve renal graft outcome, possibly through better control of the recipient's humoral immune response.

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“…Interestingly, these cases are characterized by early presentation, and are often limited to the allograft, in contrast to recipient-derived PTLD which occurs later and is disseminated more frequently [14]. Finally, there is some evidence pointing to direct oncogenic effects of specific immunosuppressive therapy [15,16].…”

Section: Pathogenesismentioning

confidence: 99%

“…Generally speaking, the risk for developing PTLD seems to be correlated with the cumulative intensity of immune suppression, although attempts have been made to determine the role of specific immunosuppressive medication. The calcineurin inhibitor cyclosporine A, for example, has been associated with a direct tumor-promoting effect by impaired DNA repair and by the production of transforming growth factor-b [15,16]. Whether cyclosporine A carries a higher risk for malignancies compared with other immunosuppressive agents remains controversial.…”

Section: Risk Factorsmentioning

confidence: 99%

Management of posttransplant lymphoproliferative disorders following solid organ transplant: an update

Dierickx¹,

Tousseyn

Wolf-Peeters

et al. 2011

Leukemia & Lymphoma

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Development of secondary malignancies is a well-known complication of solid organ transplant, with skin cancer and lymphoproliferative disorders being most frequently observed. Posttransplant lymphoproliferative disorders, caused by diminished immune surveillance, represent a broad spectrum of pathological and clinical disorders, ranging from benign conditions to very aggressive lymphomas. Here we review treatment options for adult patients experiencing posttransplant lymphoproliferative disorders following solid organ transplant.

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Molecular effects of cyclosporine and oncogenesis: a new model

Cited by 8 publications

References 0 publications

Calcineurin Inhibitors Decrease DNA Repair and Apoptosis in Human Keratinocytes Following Ultraviolet B Irradiation

Calcineurin Inhibitors Decrease DNA Repair and Apoptosis in Human Keratinocytes Following Ultraviolet B Irradiation

Maintaining calcineurin inhibition after the diagnosis of post-transplant lymphoproliferative disorder improves renal graft survival

Management of posttransplant lymphoproliferative disorders following solid organ transplant: an update

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