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

Inhibitors of the mammalian target of rapamycin are a new class of immunosuppressants. In contrast to other macrolides, such as tacrolimus and cyclosporine A, they do not inhibit calcineurin and thus signal I of T-cell activation. By inhibiting signal III, the mechanism of action and side effects of sirolimus (rapamycin) and its derivative RAD are distinct from other immunosuppressants. Reports of synergism with cyclosporine A and tacrolimus in preclinical and clinical studies, avoidance of nephrotoxicity, and possible treatment or prevention of chronic allograft rejection are leading to high expectations for this new class of immunosuppressants. Furthermore, studies evaluating tolerance induction are being conducted. This review summarizes preclinical and clinical results published to date and exploits the future value of sirolimus and RAD for clinical transplantation.
 ...
PMID:mTOR inhibitors: an overview. 1144 73

SIROLIMUS: The leading member of the mTOR inhibitor family, sirolimus or rapamycin, has dose-dependent side effects that can generally be well controlled. Sirolimus can be combined with tacrolimus at therapeutic doses; likewise for the sirolimus-cyclosporine combination at moderate dosage. Effective plasma concentrations of sirolimus vary from 5 to 20 ng/ml depending on the combination of immunosuppressant agents used. Sirolimus has been shown to inhibit metastatic diffusion of renal adenocarcinoma in the mouse. Its complex side effects on angiogenesis, fibrosis processes and chronic rejection are still being investigated. EVEROLIMUS: Everolimus, or RAD, has a very short half-life, but induces fewer hematologic effects. The therapeutic dose must reach at least 3 ng/ml to prevent rejection. Doses above 15 ng/ml increase the risk of thrombocytopenia. FTY 720: A new immunosuppressant agent, FTY 720, does not belong to any known family. It has a totally different mechanism of action compared with currently available immunosuppressants. FTY 720 increases the expression of chemokine receptors on the surface of T cells making them unavailable for the rejection reaction. FTY 720 has a very long half-life (108 hours). Due to its particular liver metabolism, there is a very low risk of drug interactions.
 ...
PMID:[mTOR and FTY 720 inhibitors]. 1157 86

Rapamycin and its derivatives, CCI-779 and RAD-001, inhibit the mammalian target of rapamycin (mTOR), downregulating translation of specific mRNAs required for cell cycle progression from G1 to S phase. Preclinically, mTOR inhibitors potently suppress growth and proliferation of numerous tumor cell lines in culture or when grown in mice as xenografts. CCI-779 and RAD-001 are being developed as antitumor drugs and are undergoing clinical trials. Clinically, CCI-779 has shown evidence of antitumor activity but induced relatively mild side effects in patients. Here we discuss potential antitumor mechanisms and resistance mechanisms of mTOR inhibitors, and summarize the current status of these compounds as novel antitumor agents.
 ...
PMID:Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. 1202 63

The mammalian target of rapamycin (mTOR), a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway that mediates cell survival and proliferation, is a prime strategic target for anticancer therapeutic development. By targeting mTOR, the immunosuppressant and antiproliferative agent rapamycin inhibits signals required for cell cycle progression, cell growth, and proliferation. Both rapamycin and novel rapamycin analogues with more favorable pharmaceutical properties, such as CCI-779, RAD 001, and AP23573, are highly specific inhibitors of mTOR. In essence, these agents gain function by binding to the immunophilin FK506 binding protein 12 and the resultant complex inhibits the activity of mTOR. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1, rapamycin-like compounds block the actions of these downstream signaling elements, which results in cell cycle arrest in the G1 phase. Rapamycin and its analogues also prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which potentially contribute to the prominent inhibitory effects of rapamycin at the G1/S boundary of the cell cycle. Rapamycin and rapamycin analogues have demonstrated impressive growth-inhibitory effects against a broad range of human cancers, including breast cancer, in preclinical and early clinical evaluations. In breast cancer cells, PI3K/Akt and mTOR pathways seem to be critical for the proliferative responses mediated by the epidermal growth factor receptor, the insulin growth factor receptor, and the estrogen receptor. Furthermore, these pathways may be constitutively activated in cancers with many types of aberrations, including those with loss of PTEN suppressor gene function. Therefore, the development of inhibitors of mTOR and related pathways is a rational therapeutic strategy for breast and other malignancies that possess a wide range of aberrant molecular constituents. This review will summarize the principal mechanisms of action of rapamycin and rapamycin derivatives, as well as the potential utility of these agents as anticancer therapeutic agents with an emphasis on breast cancer. The preliminary results of early clinical evaluations with rapamycin analogues and the unique developmental challenges that lie ahead will also be discussed.
 ...
PMID:Mammalian target of rapamycin: a new molecular target for breast cancer. 1286 41

The mammalian target of rapamycin (mTOR) is a downstream protein kinase of the phosphatidylinositol 3'-kinase-Akt signalling pathway. As a result of its position within this pathway and its central role in controlling cellular growth, mTOR is viewed as an important target for anticancer therapeutics development. Currently, the mTOR inhibitor rapamycin (sirolimus, Wyeth) and its derivatives temsirolimus (CCI-779, Wyeth), everolimus (RAD-001, Novartis Pharma AG) and AP-23573 (Ariad Pharmaceuticals) are being evaluated in cancer clinical trials. Preclinical studies suggest that sensitivity to mTOR inhibition may correlate with aberrant activation of the phosphatidylinositol 3'-kinase pathway and/or with aberrant expression of cell-cycle regulatory or antiapoptotic proteins. Clinical trial results show that mTOR inhibitors are generally well tolerated and may induce prolonged stable disease and even tumour regressions in a subset of patients. Questions remain regarding optimal dose, schedule, patient selection and combination strategies for this novel class of agents.
 ...
PMID:Inhibitors of the mammalian target of rapamycin. 1583 62

The immunosuppressive macrolide rapamycin and its derivative everolimus (SDZ RAD, RAD) inhibit the mammalian target of rapamycin (mTOR) signaling pathway. In this study, we provide evidence that RAD has profound antiproliferative activity in vitro and in NOD/SCID mice in vivo against Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) cells. Moreover, we identified 2 molecular mechanisms that showed how RAD exerts antiproliferative effects in HL and ALCL cells. RAD down-regulated the truncated isoform of the transcription factor CCAAT enhancer binding protein beta (C/EBPbeta), which is known to disrupt terminal differentiation and induce a transformed phenotype. Furthermore, RAD inhibited constitutive nuclear factor kappaB (NF-kappaB) activity, which is a critical survival factor of HL cells. Pharmacologic inhibition of the mTOR pathway by RAD therefore interferes with essential proliferation and survival pathways in HL and ALCL cells and might serve as a novel treatment option.
 ...
PMID:A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein {beta} and NF-{kappa}B activity in Hodgkin and anaplastic large cell lymphomas. 1588 25

Apoptosis, or programmed cell death, is a mechanism by which cells undergo death to control cell proliferation or in response to DNA damage. The understanding of apoptosis has provided the basis for novel targeted therapies that can induce death in cancer cells or sensitize them to established cytotoxic agents and radiation therapy. These novel agents include those targeting the extrinsic pathway such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1, and those targeting the intrinsic Bcl-2 family pathway such as antisense bcl-2 oligonucleotides. Many pathways and proteins control the apoptosis machinery. Examples include p53, the nuclear factor kappa B, the phosphatidylinositol 3 kinase pathway, and the ubiquitin/proteosome pathway. These can be targeted by specific modulators such as bortezomib, and mammalian target of rapamycin inhibitors such as CCI-779 and RAD 001. Because these pathways may be preferentially altered in tumor cells, there is potential for a selective effect in tumors sparing normal tissue. This article reviews the current understanding of the apoptotic pathways, including the extrinsic (cytoplasmic) and intrinsic (mitochondrial) pathways, and the agents being developed to target these pathways.
 ...
PMID:Targeting apoptosis pathways in cancer therapy. 1589 Jun 40

Tubulointerstitial fibrosis is largely mediated by (myo)fibroblasts present in the interstitium. In this study, we investigated the role of mTOR and phosphatidylinositol 3-kinase in the regulation of fibroblast kinetics, fibroblast differentiation, and collagen synthesis. Rat renal fibroblasts were propagated from kidneys 3 days post-ureteric obstruction and specific inhibitors of mTOR (RAD) and phosphatidylinositol 3-kinase (LY294002) were used to examine the regulation of fibrogenesis. LY294002 but not RAD completely inhibited phosphorylation of Akt, while both inhibitors decreased phosphorylation of the S6 ribosomal protein. RAD and LY decreased foetal calf serum stimulated proliferation and DNA synthesis. In addition to their individual effects, treatment with both RAD and LY294002 decreased serum-induced fibroblast proliferation and DNA synthesis significantly more than either drug alone. TUNEL positive cells (apoptosis) in RAD and LY294002 treated groups were not different from control groups. In addition to their effect on proliferation, both inhibitors also reduced total collagen synthesis. Differentiation studies indicated an increase in alpha-smooth muscle actin expression relative to beta-actin (western blotting), with cytochemistry confirming that all doses of RAD and LY294002 increased the proportion of alpha-smooth muscle actin positive cells, and hence myofibroblasts. Effects were independent of cell toxicity. These results highlight the potential significance of PI3K and mTOR, in the regulation of renal (myo)fibroblast activity. The synergistic effects of LY and RAD on proliferation suggest that mTOR signalling involves pathways other than phosphatidylinositol 3-kinase. These results provide a novel insight into the mechanisms of fibroblast regulation during fibrogenesis.
 ...
PMID:Role of the phosphatidylinositol 3-kinase and mTOR pathways in the regulation of renal fibroblast function and differentiation. 1697 6

The mammalian target of rapamycin (mTOR) is a key element of the PI3KAkt (protein kinase B) signalling pathway, responsible for the regulation of cell growth and proliferation. There are two main downstream messengers of the mTOR kinase, eukaryotic initiation factor 4E-binding protein-1 and the 40S ribosomal protein S6 kinase 1, that control translation and cell-cycle progression. Abnormal activation of the mTOR pathway occurs frequently in numerous human malignancies; therefore, mTOR represents an attractive target for anticancer drug development. Rapamycin and its analogues CCI-779, RAD-001 and AP-23573 are known specific inhibitors of the mTOR kinase. Several clinical Phase I/II trials showed their activity in solid tumours and haematological malignancies. Moreover, inhibitors of mTOR were found to synergise with some cytostatics or other biological agents, which seems to be a promising direction for future strategies of antitumour treatment.
 ...
PMID:Investigating mammalian target of rapamycin inhibitors for their anticancer properties. 1698 97

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection.
 ...
PMID:Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. 1816 98


1 2 3 Next >>