Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrolides are xenobiotics, produced by soil fungi, which have immunosuppressant properties. They will probably revolutionise the treatment of inflammatory dermatoses. This article outlines the context and putative mechanisms of action of this novel class of drugs. Cyclosporin, and the structurally distinct macrolides tacrolimus and pimecrolimus (an ascomycin derivative), modulate immune-cell function by inhibiting calcineurin-dependent dephosphorylation-activation of specific nuclear factors, thus preventing transcription of pro-inflammatory cytokines. The macrolide rapamycin (sirolimus) acts by abrogating Target of Rapamycin, a key signalling protein that controls activation of a number of proteins which direct progression of the cell cycle in response to pro-inflammatory cytokines. Tacrolimus and pimecrolimus are small enough molecules to penetrate skin and are available in topical formulations. "Skin-specific" pimecrolimus seems not to cause systemic immunosuppression when given orally. Neither topical tacrolimus nor pimecrolimus are capable of producing skin atrophy. Sirolimus has anti-angiogenic properties that may be beneficial to the treatment of psoriasis and perhaps skin cancer.
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PMID:The macrolide immunosuppressants in dermatology: mechanisms of action. 1245 45

The incidence of malignancy was estimated in 1055 renal transplant recipients, engrafted between 1983 and 2001 including 611 grafts from living and 444 from cadaveric donors. The meoplasms were 22 skin cancers, 18 Kaposi's sarcomas, 10 lymphomas nine non-Hodgkin's and one Hodgkin's lymphoma) and 24 visceral carcinomas. Skin cancers were completely excised. Patients with Kaposi sarcoma were treated by tapering the immunosuppression with cessation of cyclosporine. In addition, four patients received chemotherapy, and one of them received local radiotherapy. All patients with lymphomas were treated by cessation of calcineurin inhibitors with modulation of the immunosuppression to levels that were safe for the graft. Furthermore, five patients underwent first line chemotherapy, two patients radiotherapy and two patients, surgical removal of the tumor. The patients with visceral tumors were treated surgically with excision of the lesions when possible, without severe modification of the immunosuppressive regimen. Chemotherapy or radiotherapy was added accordingly. Disease-related mortality rate in patients with skin cancer was 4.5%; in Kaposi's Sarcoma cases 11.11%; in lymphomas 50%; and in all the other instances, 45.8%. This study shows the increased incidence of certain malignancies in transplant recipients, illustrating the importance of cancer surveillance following kidney transplantation. A substantial reduction or even cessation of immunosuppressive therapy may be necessary to achieve patient survival.
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PMID:Study of "de novo" malignancies among greek renal transplant recipients. 1282 71

Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.
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PMID:[Topical immunomodulators in dermatology]. 1290 53

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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PMID:Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation. 1802 38

Calcineurin inhibitors are drugs used to suppress the immune system by blocking the nuclear localization of the NFAT transcription factor. Systemic use of these drugs is essential to organ transplantation, but comes at the cost of elevated rates of skin cancer. They have been used topically in atopic dermatitis and other skin diseases on the assumption that they avoid the cancer risk by localized use. The results here show that in skin cells and artificial models of human skin, calcineurin inhibitors block UV-induced nuclear localization of NFAT, and significantly reduce repair of cyclobutane pyrimidine dimers induced in DNA. In addition they inhibit apoptosis of UV-irradiated cells. The effect of blocking nuclear localization of NFAT and inhibiting DNA repair should be considered in judging the risk of topical use of calcineurin inhibitors.
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PMID:Calcineurin inhibitors reduce nuclear localization of transcription factor NFAT in UV-irradiated keratinocytes and reduce DNA repair. 1692 98

Cancer has been reported to be more common among kidney transplant recipients than waiting-list patients or the general population. Use of anticalcineurin agents and azathioprine are relevant risk factors. Nine renal allograft recipients (seven men and two women) of mean age 67.6 (55-77) years and mean time after transplantation of 30.7 (58-216) months were switched to everolimus-based immunosuppression because of the presence of biopsy-proven malignancies (eight patients) or neurological tacrolimus toxicity (one patient). One patient with posttransplant lymphoproliferative disease also received chemotherapy with a good evolution at 6 months. He showed an initial increase in the protein to creatinine ratio (peak 3.3 mg/mg at 3 months) that was controlled by increasing the enalapril dose. One patient with skin cancer and severe atheromatosis (baseline SCr 2.5 mg/dL, creatinine clearance 17 mL/min, and protein to creatinine ratio 3.2 mg/mg), had cyclosporine and everolimus overlapped for 25 days, showing a continued poor evolution requiring dialysis initiation at 3 months after switch. The other six patients with recurrent skin cancers had good cancer evolution, with no new skin tumors and regression of skin lesions in three, including not biopsied actinic keratosis. Sudden switching from calcineurin inhibitors to everolimus is safe and may be used in long-term transplant recipients with malignancies. In patients with advanced chronic nephropathy this approach appeared to be less beneficial.
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PMID:Conversion from calcineurin inhibitors to everolimus in kidney transplant recipients with malignant neoplasia. 1709 65

Non-melanoma skin cancer (NMSC) affects a large proportion of renal transplant recipients, with estimates suggesting that at least half of white-skinned transplant recipients will develop NMSC following transplantation. Squamous-cell carcinoma is the most frequent NMSC following transplantation occurring at a 100-times greater risk than in the general population, while the incidence of basal cell carcinoma is increased 10-fold over the general population. The most important risk factor for the development of NMSC in renal transplant recipients is prior exposure to ultraviolet radiation, therefore, geographical location and skin type highly influence the risk of NMSC. However, both the intensity and type of immuno-suppressive therapy have been associated with an increased risk of NMSC. Given the potential anti-cancer actions of the proliferation signal inhibitors (PSIs), everolimus and sirolimus, demonstrated in both pre-clinical and clinical studies, we have analysed the effect of conversion to PSIs in 53 renal transplant recipients developing NMSC after transplantation. Remission of NMSC was observed in 37 patients and was generally well tolerated with minimal adverse events reported. Fifteen patients developed new lesions following conversion, two of these were receiving low-dose calcineurin inhibitors (CNIs) as part of their immuno-suppressive regimen suggesting that there was insufficient reduction of CNIs. PSI blood levels did not seem to affect the outcomes of conversion. These data, along with published clinical trial data suggest that conversion from CNIs to PSIs may be useful in the management of NMSC following renal transplantation.
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PMID:Use of proliferation signal inhibitors in non-melanoma skin cancer following renal transplantation. 1745 15

In this review the controversy regarding the association between topical pimecrolimus and tacrolimus and the development of tumors is unfolded. After reviewing the literature we conclude that, currently, there is no scientific evidence of an increased incidence of skin cancer, lymphomas or systemic immunosuppression in those patients that use or have used topical calcineurin inhibitors. Published studies lack adequate number of patients and/or the follow-up time is short enough to conclude that topical use of calcineurin inhibitors might be associated with the reported cases of skin cancer and lymphoma. Nevertheless the possibility of long term cutaneous and/or systemic side effects cannot be excluded.
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PMID:[Topical pimecrolimus and tacrolimus and the risk of cancer]. 1755 73

Renal transplant recipients are at higher risk of certain tumors such as lymphomas and skin cancers and than the general and dialysis populations. We retrospectively studied the prevalence of tumors in adult renal transplant recipients in four Tunisian centers of transplantation in Tunis, Monsatir and Sfax from January 1986 to January 2005. The study included 36 patients; 19 men and 17 women with a mean age of 34.6 years (range from 18-54 years). The mean time since dialysis to transplantation was 43 months (6-131months). Maintenance therapy was based on calcineurin inhibitors (CNI) in 86 % of cases, on antimetabolites and corticosteroids in 100 % of cases. Anti-thymoglobulin was administered in a mean course of 12.4 days in 78 % of the patients. Acute rejection occurred in 25 cases and was treated with polyclonal or monoclonal antibodies on 40 % of cases. Incidence of cancer among our population was 7 % and occurred after a mean period of 54 months of transplantation (range from 4-160 months). Eighty three percent of the tumors were solid, and the rest were in the skin. Kaposi sarcoma formed 41.6 % and non-Hodgkin or Hodgkin lymphoma 27.7 % of the solid tumors, while spinocellular carcinoma formed 83% and basocellular carcinoma 17% of the skin tumors. Switching CNI to sirolimus in 8.3% cases was associated with a favorable outcome. Mortality was the outcome in 33.3% of the patients with cancer, while partial or complete regression of cancers was observed in 55.5% cases after decreasing the doses of the immunosuppressive medications. We conclude that post renal transplant cancer is mainly characterized by the predominance of Kaposi sarcoma favored by solar exposure and rigorously induced and maintained immunosuppression. Careful follow-up may results in early intervention and decrease mortality.
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PMID:Cancers after renal transplantation: multicenter experience. 1871 9

Skin cancers are the most common tumors among transplant recipients who receive immunosuppressive agents. Kaposi sarcoma (KS) is one of the most common malignancies to occur in kidney transplant recipients, especially in the Middle East countries. Its prevalence in comparison with other neoplasms is also relatively higher in Iran (> 35%). The KS-associated herpesvirus or human herpesvirus 8 is a newly discovered herpesvirus found in all forms of the KS including those among immunosuppressed transplant recipients. Kaposi sarcoma usually regresses after withdrawal or reduction of immunosuppressive agents. A wide variety of therapies have been used for KS, including radiotherapy and administration of interferon and different chemotherapeutic regimens. Sirolimus exhibits antiangiogenic activity related to impaired production of vascular endothelial growth factor and limited proliferative response of endothelial cells to the stimulation by vascular endothelial growth factor. Therefore, it can inhibit the progression of KS. Accordingly, replacement of calcineurin inhibitors by a sirolimus can show promising results in the prevention of KS.
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PMID:Kaposi sarcoma after kidney transplantation. 1935 36


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