Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Post-transplant malignancy is recognised as being a major limitation to the success of solid organ transplantation and it is currently considered one of the unavoidable costs of long-term immunosuppressive therapy. However, the continual introduction of new immunosuppressive drugs and the growing knowledge about their different oncogenic profiles, requires a continuous evaluation of the available evidence on this topic. The incidence and risk of malignancy is elevated in solid organ transplant recipients compared with the general population. As proof of the relationship between immunosuppressive therapy and post-transplant malignancy, epidemiological data reveal that the length of exposure to immunosuppressive therapy and the intensity of therapy are clearly related to the post-transplant risk of malignancy, and that once cancer has developed, more intense immunosuppression can translate into more aggressive tumour progression in terms of accelerated growth and metastasis and lower patient survival. The association between malignancy and immunosuppressive therapy is mediated through several pathogenic factors. Indirectly, immunosuppressive drugs greatly increase the post-transplant risk of malignancy by impairing cancer surveillance and facilitating the action of oncogenic viruses. However, the direct pro- and anti-oncogenic actions of immunosuppressants also play an important role. The cancer-promoting effect of calcineurin inhibitors, independently of depressed immunosurveillance, has been demonstrated in recent years, and currently only mammalian target of rapamycin (mTOR) inhibitors have shown simultaneous immunosuppressive and antitumour properties. Reports of the initial results of the reduced incidence of cancer in organ transplant recipients receiving mTOR inhibitor therapy strongly indicate separate pathways for pharmacological immunosuppression and oncogenesis. The role of mTOR inhibitors has been firmly established for the treatment of post-transplant Kaposi's sarcoma and its role in the management of patients with other post-transplant malignancies should be clarified as soon as possible. Prevention of morbidity and mortality resulting from post-transplant malignancy should become a main endpoint in solid organ transplant programmes, and the choice and management of immunosuppressive therapy in each phase of transplantation plays a central role in this objective. Although comprehensive and rigorous information about the management of immunosuppressive therapy in transplant recipients at risk of or affected by cancer is still lacking, new experimental and clinical data about mTOR inhibitors offers novel approaches to this problem.
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PMID:Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. 1752 Dec 18

Discovered in fungi in the remote Easter Island, sirolimus (rapamycin) shows potential beyond its obvious antiproliferative and immunosuppressant activity. Studies have demonstrated that sirolimus acts as a vascular endothelial growth factor inhibitor, providing prospective therapeutic benefits and possible prevention of tuberous sclerosis and Kaposi's sarcoma. Its ability to decrease keratinocyte proliferation may help patients with psoriasis. In those with tuberous sclerosis complex, it may prevent the development of hamartomas and reduce or eliminate them once grown by blocking the mammalian target of rapamycin, a critical regulatory kinase. A great advantage for this drug is in the decreased risk of malignancies, including Kaposi's sarcoma, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors. This review will focus on the pharmacology and potential uses of sirolimus.
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PMID:Sirolimus (rapamycin): from the soil of Easter Island to a bright future. 1758 72

The most frequent causes of late kidney allograft failure are chronic rejection, nonalloimmune injury and death, all of which may depend on the characteristics of the donor and recipient, but may also be influenced by the type of immunosuppression. Combining calcineurin inhibitors (CNIs) and corticosteroids offers potent immunosuppression, but may also cause side effects leading to progressive graft dysfunction or an increased risk of death. New immunosuppressive strategies may come from the availability of inhibitors of mTOR, a downstream effector of phosphatidylinositol-3 kinase that provides the signal for cell proliferation by phosphorylating a cascade of kinases. Recent trials have shown that it is possible to minimize the dose or withdraw CNIs a few weeks after transplantation when they are combined with mTOR inhibitors and their combination may also make it possible to minimize or avoid the use of corticosteroids. Moreover, by inhibiting the signal for cell proliferation, mTOR inhibitors may reduce the replication of cytomegalovirus inside host cells, prevent transplant vasculopathy, and exert anti-oncogenic activity. All of these characteristics offer a ray of hope for reducing the risk of long-term allograft failure.
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PMID:Can mTOR inhibitors reduce the risk of late kidney allograft failure? 1763 37

The mTOR (mammalian target of rapamycin) inhibitors sirolimus (SRL) and everolimus (EVL) are potent immunosuppressive agents, which allow reducing the dose of the nephrotoxic calcineurin inhibitors cyclosporin and tacrolimus (TAC) in solid organ transplant recipients. However, there is evidence that mTOR inhibitors may lead to myelosuppression and dyslipidemia/hyperlipidemia. We therefore performed a retrospective analysis in heart transplant recipients with renal insufficiency, who received 3.0 mg/d SRL (SRL group; n = 28) or 1.5 mg/d EVL (EVL group; n = 27) each in combination with a reduced TAC dose for at least one yr. Fewer cardiac rejections, but a similar rate of infections occurred in the EVL group compared with the SRL group indicating that the administered EVL dose resulted in a potent immunosuppression. Serum triglyceride and total cholesterol concentrations rose significantly in the SRL group but not in the EVL group. In the SRL group only, the frequency of statin use increased significantly during follow-up. The EVL group showed a significant rise in HDL cholesterol levels during follow-up. There was a slight transient fall in haemoglobin concentrations in the SRL group but not in the EVL group. Leucocyte counts fell significantly in both study groups. However, no cases of leucopenia and also no cases of thrombopenia occurred. In summary, we could demonstrate that in heart transplant recipients with renal insufficiency the introduction of 1.5 mg/d EVL in combination with a reduced TAC dose is effective in preventing cardiac rejections and has less adverse effects on lipid metabolism than the usually prescribed SRL dose, whereas both therapy regimens are not associated with major haematological side-effects.
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PMID:Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart transplant recipients. 1764 16

Cyclosporine (CsA), a member of the family of calcineurin inhibitors, is a cornerstone of the immunosuppressive treatments used after organ transplantation. However, it exhibits significant toxicity, including nephrotoxicity and increased cardiovascular risk factors. CsA withdrawal has been used as a strategy to improve renal allograft function and other CsA-related toxicities. In order to maintain adequate immunosuppression levels, sirolimus may be used in association with CsA withdrawal. Sirolimus is a member of the mammalian target of rapamycin (mTOR) family. It presents a good immunosuppressive efficacy associated with antiproliferative actions. Early withdrawal of CsA with sirolimus is associated with a significant improvement of renal function. Despite numerically a higher incidence of acute rejection episodes, this maneuver seems also to be associated with a better allograft survival in the long-term, and improvement of renal histology and blood pressure. However, CsA withdrawal is only feasible in a selected population. Furthermore, the use of sirolimus is associated with other side-effects including lipid abnormalities, abnormal liver tests, and thrombocytopenia. Other studies are mandatory to define the population who can benefit from this maneuver. Finally, complete CsA avoidance has been already reported and is currently under clinical investigation.
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PMID:Sirolimus therapy following early cyclosporine withdrawal in transplant patients: mechanisms of action and clinical results. 1771 68

Acute rejection episodes are now as low as 5-20% in the first year after renal transplantation; however, graft half-life has remained almost unchanged in the last decade. This statistic is mainly attributable to the side effects of immunosuppression, with loss of allografts due to the chronic allograft nephropathy that is a consequence of calcineurin inhibitor toxicity or hypertension. Patient death due to cardiovascular events, infections and malignancy also contribute to allograft loss. The introduction of the inhibitors of the mammalian target of rapamycin sirolimus and everolimus in renal transplantation has increased the repertoire of immunosuppressive protocols substantially. They have a different mode of action and a different side effect profile (i.e. lower nephrotoxicity, less hypertension and less neoplastic potential) than the calcineurin inhibitors. The inhibitors of the mammalian target of rapamycin therefore provide an especially promising alternative for the maintenance immunosuppression after renal transplantation. This overview provides a summary of the current literature on inhibitors of the mammalian target of rapamycin, with a special focus on sirolimus.
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PMID:Sirolimus in renal transplantation. 1789 Feb 66

In smooth muscle, the ryanodine receptor (RyR) mediates Ca(2+) release from the sarcoplasmic reticulum (SR) Ca(2+) store. Release may be regulated by the RyR accessory FK506-binding protein (FKBP12) either directly, as a result of FKBP12 binding to RyR, or indirectly via modulation of the activity of the phosphatase calcineurin or kinase mTOR. Here we report that RyR-mediated Ca(2+) release is modulated by FKBP12 in colonic but not aortic myocytes. Neither calcineurin nor mTOR are required for FKBP12 modulation of Ca(2+) release in colonic myocytes to occur. In colonic myocytes, co-immunoprecipitation techniques established that FKBP12 and calcineurin each associated with the RyR2 receptor isoform (the main isoform in this tissue). Single colonic myocytes were voltage clamped in the whole cell configuration and cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) increases evoked by the RyR activator caffeine. Under these conditions FK506, which displaces FKBP12 (to inhibit calcineurin) and rapamycin, which displaces FKBP12 (to inhibit mTOR), each increased the [Ca(2+)](c) rise evoked by caffeine. Notwithstanding, neither mTOR nor calcineurin are required to potentiate caffeine-evoked Ca(2+) increases evoked by each drug. Thus, the mTOR and phosphatidylinositol 3-kinase inhibitor, LY294002, which directly inhibits mTOR without removing FKBP12 from RyR, did not alter caffeine-evoked [Ca(2+)](c) transients. Nor did inhibition of calcineurin by cypermethrin, okadaic acid or calcineurin inhibitory peptide block the FK506-induced increase in RyR-mediated Ca(2+) release. In aorta, although RyR3 (the main isoform), FKBP12 and calcineurin were each present, RyR-mediated Ca(2+) release was unaffected by either FK506, rapamycin or the calcineurin inhibitors cypermethrin and okadaic acid in single voltage clamped aortic myocytes. Presumably failure of FKBP12 to associate with RyR3 resulted in the immunosuppressant drugs (FK506 and rapamycin) being unable to alter the activity of RyR. The effects of these drugs are therefore, apparently dependent on an association of FKBP12 with RyR. Together, removal of FKBP12 from RyR augmented Ca(2+) release via the channel in colonic myocytes. Neither calcineurin nor mTOR are required for the FK506- or rapamycin-induced potentiation of RyR Ca(2+) release to occur. The results indicate that FKBP12 directly inhibits RyR channel activity in colonic myocytes but not in aorta.
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PMID:FK506-binding protein (FKBP12) regulates ryanodine receptor-evoked Ca2+ release in colonic but not aortic smooth muscle. 1795 Aug 43

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.
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PMID:Anticancer effect of sirolimus in renal allograft recipients with de novo malignancies. 1802 73

The domain of solid organ transplantation is characterized by the use of variable drug combinations with drug-drug interactions, and the presence of two genomes, that of the transplanted organ and that of the receiver, which can be involved in the pharmacogenetics of these drugs. This paper is a literature review of the impact of the genetic polymorphisms of the metabolic enzymes, efflux transporters and therapeutic targets of the main immunosuppressive drugs (cyclosporine, tacrolimus, sirolimus and mycophenolate) on the dose-concentration and concentration-effect relationships of these drugs. The polymorphisms of metabolic enzymes have significant effects on the pharmacokinetics of all these drugs, but the clinical trials for validating treatment individualization based on these genetic differences are still lacking. It should be noted that the influence of the donor's genome has seldom been studied and has been found to be significant in liver transplant recipients. The influence of efflux transporter genes polymorphisms, in particular of P-glycoprotein and MPR2, is controversial. As for the polymorphisms of the drug targets genes, either they have not been reported (calcineurin, mTOR), or their influence has only been the subject of a few preliminary studies (IMPDH2). The pharmacogenetics of immunosuppressants is thus still an open field for investigations and potential therapeutic progress.
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PMID:[Pharmacogenetics and immunosuppressor drugs: impact and clinical interest in transplantation]. 1807 70

Among the immunosuppressive drugs currently used in solid-organ transplantation, the calcineurin inhibitors cyclosporine and tacrolimus, and the mammalian target of rapamycin inhibitors sirolimus and everolimus, may be difficult to use because of large interindividual variability in their pharmacokinetic characteristics and a narrow therapeutic index. The promise of pharmacogenetics and pharmacogenomics is to elucidate the inherited basis of differences between individual responses to drugs, in order to identify the right drug and dose for each patient. As cytochrome P450 (CYP)3A4 and CYP3A5 are both involved in the metabolism of these drugs, the consequences of the polymorphism of these genes have been studied. It has been recently shown that the CYP3A5*3 polymorphism is associated with pharmacokinetics of tacrolimus and sirolimus. The association between the CYP3A4 and CYP3A5 polymorphisms and cyclosporine pharmacokinetics is more questionable. It is now of utmost importance to prospectively test these initial results to improve the individualized use of these drugs.
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PMID:Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. 1824 Sep 9


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