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)

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.
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PMID:Benefit-risk assessment of sirolimus in renal transplantation. 1569 Dec 25

The Akt kinases promote hematopoietic cell growth and accumulation through phosphorylation of apoptotic effectors and stimulation of mTOR-dependent translation. In Akt-transformed leukemic cells, tumor growth can be inhibited by the mTOR inhibitor rapamycin, and clinical trials of rapamycin analogs for the treatment of leukemia are under way. Surprisingly, nontransformed hematopoietic cells can grow and proliferate in the presence of rapamycin. Here, we show that Pim-2 is required to confer rapamycin resistance. Primary hematopoietic cells from Pim-2- and Pim-1/Pim-2-deficient animals failed to accumulate and underwent apoptosis in the presence of rapamycin. Although animals deficient in Akt-1 or Pim-1/Pim-2 are viable, few animals with a compound deletion survived development, and those that were born had severe anemia. Primary hematopoietic cells from Akt-1/Pim-1/Pim-2-deficient animals displayed marked impairments in cell growth and survival. Conversely, ectopic expression of either Pim-2 or Akt-1 induced increased cell size and apoptotic resistance. However, though the effects of ectopic Akt-1 were reversed by rapamycin or a nonphosphorylatable form of 4EBP-1, those of Pim-2 were not. Coexpression of the transgenes in mice led to additive increases in cell size and survival and predisposed animals to rapid tumor formation. Together, these data indicate that Pim-2 and Akt-1 are critical components of overlapping but independent pathways, either of which is sufficient to promote the growth and survival of nontransformed hematopoietic cells.
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PMID:Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. 1570 89

Everolimus is a proliferation signal inhibitor (PSI)/mammalian target of rapamycin inhibitor that is structurally similar to sirolimus, but with a number of important pharmacokinetic differences, including a shorter half-life and time to steady state. In clinical trials, the efficacy of everolimus 1.5 mg/day and 3.0 mg/day combined with ciclosporin (CsA) and steroids in de novo renal transplant recipients is similar to that of mycophenolate mofetil, with one study showing a significantly lower risk of antibody-treated acute rejection with everolimus. When combined with reduced-dose CsA, everolimus is associated with improved renal function compared with full-dose CsA, with no decrease in efficacy. Thus, everolimus may play an important role in calcineurin inhibitor (CNI)-sparing regimens for renal transplant recipients. Studies with sirolimus have shown that CNI withdrawal is associated with a significant improvement in renal function, although there may be an increase in the risk of acute rejection. however, patient and graft survival are not adversely affected by CNI withdrawal. Notably, proteinuria <800 mg/day before conversion is a strong predictor of successful response to sirolimus treatment, and hypertensive therapy and serum lactate dehydrogenase levels may also predict response. Adverse events commonly associated with the PSIs include dyslipidaemia, proteinuria and anaemia, although these can usually be managed without difficulty. Data are also available to suggest that the PSIs are associated with a lower risk of malignancy than other immunosuppressive agents. In conclusion, everolimus may permit reduced exposure to CNIs in renal transplant recipients, with the potential to improve tolerability and renal function.
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PMID:Everolimus in clinical practice--renal transplantation. 1681 52

Calcineurin inhibitors (CNIs) are associated with important side effects, such as nephrotoxicity, and thus there is an interest in developing CNI-sparing protocols using agents such as the proliferation signal inhibitor/mammalian target of rapamycin inhibitor everolimus. In a 3-month pilot study using an abrupt conversion protocol, ciclosporin (CsA) treatment was stopped after the morning dose and everolimus was started at 3.0 mg/day. Mycophenolic acid (MPA)-based therapy was continued, or prednisolone increased to 10 mg/day until target everolimus trough blood levels (3-8 ng/ml) were achieved. To date, seven patients have been enrolled, with three having completed at least 3 months of follow-up. Overall, conversion was effective and well-tolerated. Patients consistently achieved everolimus trough blood levels >3 ng/ml, and no episodes of acute rejection or proteinuria were reported after 3 months. In patients who completed the study, there were no major changes in the leucocyte or platelet counts during everolimus treatment. Serum creatinine levels were maintained or decreased slightly. One patient experienced a transient increase in serum creatinine during an episode of pneumonia, but levels decreased again after resolution of infection and temporary everolimus dose reduction. Serum cholesterol and triglyceride levels increased, but remained within acceptable limits. One patient receiving enteric-coated mycophenolate sodium 1440 mg/day experienced increasing everolimus trough blood levels and anaemia after conversion, and was therefore likely to have been over-immunosuppressed. Abrupt conversion to everolimus from CsA was effective and well-tolerated in renal transplant recipients. A reduction in MPA dosage at the time of conversion may be necessary to prevent over-immunosuppression.
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PMID:Conversion to everolimus in maintenance patients--current clinical strategies. 1681 53

Erythropoietin (Epo) is used commonly to treat cancer and/or therapy-related anemia. Until recently, Epo was considered to be a specific stimulator of erythropoiesis, acting via its receptor, EpoR. It becomes clear, however, that EpoR is expressed in a variety of cell types other than hematopoietic cells, and that Epo is a potent cytoprotective cytokine increasing cell survival under hypoxic conditions. Epo and EpoR are also expressed in various malignant tumors, and EpoR expression shows association with tumor invasion and progression. Recently, a functional Epo autocrine signaling mechanism was also detected in human melanoma cells. In this study, we examined the hypothesis that Epo activates the Akt signaling pathway in human melanoma cells and thus promotes the survival of tumor cells. The Akt signaling pathway in response to Epo was examined in melanoma. Similar to Epo, the expression of EpoR was up-regulated in response to hypoxia and Epo stimulation in melanoma cells. Melanoma cells constitutively expressed Akt with variable expression of mammalian target of rapamycin, and Epo dose-dependently induced their activity. Epo increased Akt kinase activity, which was abrogated by co-treatment with LY294002, a specific blocker of phosphoinositide 3-kinase. LY294002 also inhibited the cytoprotective effects of Epo in melanoma cells under both normoxic and hypoxic conditions. Our results suggest that Epo promotes melanoma cell survival by activating an Akt-dependent signaling pathway.
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PMID:Erythropoietin activates the phosphoinositide 3-kinase/Akt pathway in human melanoma cells. 1684 23

Sirolimus is a potent immunosuppressant drug with a novel mechanism of action. It inhibits the mammalian target of rapamycin (mTOR) and blocks the cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus is widely used as a maintenance immunosuppressive agent in organ transplantation. Also, a potentially benefit of this valuable drug in some immunologic and malignant diseases is currently under scrutiny.Classical side effects: hematological (anaemia, leucopenia, thrombocytopenia), hypercholesterolemia, arthralgias, extremity oedema and impaired wound healing have been frequently associated with the use of sirolimus. Additionally with its increased use, transplant professionals are encountering a variety of previously unreported and potentially more severe side effects.Here, we review the most recent data on sirolimus unexpected side effects (with an emphasis on pulmonary and renal toxicity), its use in renal transplantation and its new potential therapeutic indications (chronic glomerulopathies, polycystic kidney disease, different types of cancer). A brief description of the current knowledge of sirolimus therapeutic drug monitoring, methods of analysis, pharmacokinetics and drug interactions with calcineurin inhibitors is also included.
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PMID:Sirolimus--challenging current perspectives. 1703 68

Constitutive activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway is observed in up to 70% of acute myelogenous leukemia. To investigate the relevance of an intrinsic PI3K-AKT pathway activation in hematopoietic malignancies, we analysed the effect of point mutations in the catalytic (p110alpha) and regulatory (p85alpha) subunit of class IA PI3K. We demonstrated that mutations in the helical (E542K, E545A) and kinase domain (H1047R) of p110alpha constitutively activate the PI3K-AKT pathway and lead to factor-independent growth of early hematopoietic cells. Proliferation and survival of the cells were inhibited in a time- and dose-dependent manner using either PI3K or AKT inhibitors. The mammalian target of rapamycin (mTOR) was demonstrated to be important for mitogenic, but not antiapoptotic signaling of mutant p110alpha. In a syngenic mouse model, hematopoietic cells expressing mutated p110alpha induced a leukemia-like disease characterized by anemia, neoplastic infiltration of hematopoietic organs and 90% mortality within 5 weeks, whereas activated mutants of the receptor tyrosine kinase c-KIT led to 100% mortality within 10 days. Our data show that point mutations in the p110alpha subunit of class IA PI3K confer factor independence to hematopoietic cells in vitro and leukemogenic potential in vivo, but have lower transforming activity than a deregulated class III receptor tyrosine kinase.
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PMID:Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells. 1831 50

Over the course of 15 years the use of sirolimus, a macrocyclic lactone, has evolved from an adjunct to calcineurin inhibitors (CNI) to the foundation of therapy due to the drug's unique properties: First, it displays synergistic pharmacodynamic interactions with CNI. Even among high immunologic risk patients, this regimen attenuates the risk of acute allograft rejection episodes when used in combination with cyclosporine or tacrolimus. Indeed >80% reduction in CNI exposure de novo yields better long-term renal function than full cyclosporine (CsA) doses, a useful tradeoff, despite the augmented occurrence of lymphoceles and impaired wound healing. Second, by inhibiting mammalian target of rapamycin (mTOR), it exerts profound anti-neoplastic effects reducing the incidence and mediating the regression of tumors displaying PTEN-deletions and/or Akt-activations in transplant and non-transplant patients. Third, it is relatively non-nephrotoxic although it may exacerbate that property of CNI agents. Fourth, it allows prompt withdrawal of steroid therapy. Fifth, it displays reduced rates of cytomegalovirus, and BK virus infections. The major adverse reactions can generally be controlled with countermeasure therapy. Myelosuppressive effects, which tend to be transient (unless sirolimus is combined with mycophenolic acid), are readily amenable to treatment with granulocyte colony stimulating factor for leukopenia, interleukin 11 for thrombocytopenia and erythropoietin for anemia. Combinations of statins and fibrates represent effective countermeasure therapy for hypercholesterolemia and hypertriglyceridemia, respectively. Idiosyncratic reactions include hypoxemic pulmonary toxicity, refractory edema and diarrhea. Thus, sirolimus represents the vanguard of a new class of maintenance agents for immunosuppression.
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PMID:Fifteen years of clinical studies and clinical practice in renal transplantation: reviewing outcomes with de novo use of sirolimus in combination with cyclosporine. 1910 Aug 99

Posttransplant anemia is a common problem that may hinder patients' quality of life. It occurs in 12 to 76% of patients, and is most common in the immediate posttransplant period. A variety of factors have been identified that increase the risk of posttransplant anemia, of which the level of renal function is most important. Sirolimus, a mammalian target of rapamycin inhibitor, has been implicated as playing a special role in posttransplant anemia. This review considers anemia associated with sirolimus, including its presentation, mechanisms, and management.
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PMID:Posttransplant anemia: the role of sirolimus. 1955 12

Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. These included increased abundance of the messenger RNA encoding the CDK inhibitors p16(Ink4a), p19(Arf), and p21(Cip1); a relative decrease in lymphopoiesis; and impaired capacity to reconstitute the hematopoietic system. In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and show the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.
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PMID:mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. 1993 33


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