Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conventional treatment of myelofibrosis involves a wait-and-see approach for asymptomatic patients, oral chemotherapy for the hyperproliferative forms of the disease, androgens or erythropoietin for the anaemia, and splenectomy in selected patients. Low-dose thalidomide plus prednisone is a well-tolerated therapy for the anaemia and the thrombocytopenia of myelofibrosis, whereas imatinib has shown little efficacy. Allogeneic stem cell transplantation (allo-SCT) is the only curative therapy for myelofibrosis. Its standard modality has an associated mortality of about 30% and can be applied to younger patients with high-risk disease or resistant to conventional treatment. Reduced-intensity conditioning allo-SCT involves a low mortality and is a promising therapy for patients aged 45-70 years old with the above characteristics. Autologous SCT is a palliative therapy for patients resistant to conventional treatment who lack a suitable donor. The next candidates for the treatment of myelofibrosis are the thalidomide derivatives, the proteasome inhibitors, and vascular endothelial growth factor neutralizing antibodies.
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PMID:Modern management of myelofibrosis. 1572 78

(1) First-line treatment of multiple myeloma depends first and foremost on the patient's age. There is no standard treatment for relapses and the median survival time after the first relapse is only 12 to 15 months. (2) Bortezomib, a cytotoxic agent, inhibits the 26S proteasome involved in protein breakdown in mammalian cells. It is licensed for use in myeloma after multiple treatment failure. (3) Three dose-finding studies showed some effects of 1 mg/m2 and 1.3 mg/m2 bortezomib administered twice a week for two weeks, with each course followed by a 10-day treatment-free period. It is not known whether 1.3 mg/m2 is more effective than 1 mg/m2. (4) In a non comparative trial that included 202 patients with multidrug-resistant myeloma, progression-free survival time increased to a median of 6.6 months (compared to 3.3 months after previous relapses), and the median overall survival time was 7 months in the 75% of patients who did not respond and more than 15 months in the 25% of responders. However, given the heterogeneous nature of the study population the evidence from this trial is rather weak. (5) An unblinded comparative trial including 54 patients failed to show whether bortezomib 1.3 mg/m2 was more effective than bortezomib 1 mg/m2 in terms of clinical outcome. Another comparative trial including 669 patients indicated that bortezomib was more effective than dexamethasone in terms of the median time to disease progression (5.7 months versus 3.6 months). (6) Animal studies indicate that bortezomib is cardiotoxic and neurotoxic, and that the interval between the maximal tolerated dose and the fatal dose is very small. Experience with bortezomib use is too limited to know the possible clinical repercussions of these experimental findings. (7) Adverse effects were frequent and varied in clinical trials. They included fatigue, nausea and vomiting, diarrhea, anemia, thrombocytopenia and peripheral neuropathies. They affected 30% to 60% of patients overall, and were severe in about 10% to 20% of patients. Other adverse effects included hypotension, fever, headache, pain and dehydration. (8) Bortezomib is metabolised by cytochrome P 450 isoenzyme 3A4, and this implies a high risk of drug-drug interactions. (9) Each vial of bortezomib contains more of the drug than is needed for one injection. This is not only wasteful, but also carries a risk of overdosing, with potentially serious consequences, should the entire contents be injected by mistake. (10) Bortezomib may be used as a last resort in some patients with multiple myeloma, but the individual risk-benefit balance must be carefully weighed in each case.
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PMID:Bortezomib: new drug. A last resort in myeloma: modest efficacy, major risks. 1598 89

HEMOLYTIC UREMIC SYNDROME POST-PARTUM: We describe a case of a 37-year-old woman admitted for severe renal failure to our hospital immediately after the delivery by caesarean section of twins. She had anuria, anemia, and moderate thrombocytopenia. A diagnosis of hemolytic-uremic syndrome was made. Plasma exchange was started, substitution was performed with fresh frozen plasma and eight consecutive plasmapheresis sessions were given. She received hydrocortisone and ACE inhibitors. After about fifteen days from the beginning of the illness, signs of active haemolysis disappeared and renal function was partially recovered. A genetic study demonstrated the absence of HF1 and MCP mutations but a polymorphic variant of the HF1 gene (C-257T promoter region). This polymorphism is strongly associated with non-diarrhoea-HUS (D-HUS). Post-partum HUS is quite a rare syndrome and has a poor outcome; however prompt diagnosis and efficacious therapy could save lives without clinical consequences. The excellent outcome of this patient seems to corroborate this concept.
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PMID:A post-partum hemolytic-uremic-like-syndrome in a patient with pre-eclampsia: description of a clinical case. 1642 9

Atypical hemolytic uremic syndrome (HUS) is a severe disease that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent evidence has shown that defective complement activation and defective complement control is a cause of HUS. So far, mutations in single genes coding for the cofactor and complement regulator factor H, the membrane cofactor protein (MCP/CD46), the serine protease factor I, and autoantibodies to factor H have been linked to HUS. All of these proteins affect the same enzyme the alternative pathway convertase C3bBb. This article explains how alternative pathway activation proceeds and how defective control increases activation, which ultimately leads to endothelial cell damage.
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PMID:The role of defective complement control in hemolytic uremic syndrome. 1657 89

Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.
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PMID:Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. 1679 May 5

(1) When multiple myeloma relapses more than one year after initial treatment, the median survival time is only 12 to 15 months. (2) Bortezomib is a cytotoxic agent that inhibits the 26S proteasome, a complex involved in intracellular protein breakdown in mammals. Bortezomib was initially licensed for the treatment of myeloma after multiple treatment failure; its indications were subsequently modified to include second-line treatment. (3) Second-line bortezomib therapy has not been compared with haematopoietic stem cell grafting, a treatment with documented efficacy. (4) An unblinded comparative trial involving 54 patients requiring second-line treatment showed that bortezomib at a dose of 1.3 mg/m to the 2nd power (twice a week for two weeks, followed by a 10 day rest period) was significantly more effective than a dose of 1 mg/m to the 2nd power in terms of the median survival time (not determined in the 1.3 mg group, versus 26.7 months in the 1 mg group) and the median time to disease progression (11.7 versus 4.2 months). (5) Among 251 patients in whom first-line treatment had failed, bortezomib was significantly more effective than dexamethasone: the one-year survival rate was 80% versus 66% on dexamethasone, and the progression-free survival time was 6.2 months versus 3.5 months. (6) Adverse effects occurred in 30% to 60% of patients enrolled in clinical trials, and were severe in about 10% to 20% of patients. They mainly included fatigue, nausea and vomiting, diarrhoea, anaemia, thrombocytopenia, and peripheral neuropathy. Animal studies indicated a possible risk of cardiotoxicity, and cases of cardiac arrhythmias and conduction disorders were observed in clinical trials. (7) Bortezomib is metabolised by the cytochrome P450 isoenzyme CYP3A4, with a high risk of interactions. (8) The vials contain an excessive amount of this costly drug, creating a risk of inadvertent overdose and leading to unnecessary waste. (9) In practice, bortezomib is an alternative to steroid therapy for patients with multiple myeloma in whom first-line treatment has failed and who do not qualify for stem cell grafting. The choice of treatment must be discussed with the patient, after providing thorough information on the likely benefits and risks
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PMID:Bortezomib: new indication. Second-line treatment of myeloma: limited efficacy, major risks. 1676 98

The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.
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PMID:Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. 1688 52

The haemolytic uraemic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure. HUS may be classified as either diarrhoeal-associated or non-diarrhoeal/atypical (aHUS). aHUS has recently been shown to be a disease of complement dysregulation, with 50% of cases involving the complement regulatory genes, factor H (CFH), membrane cofactor protein (MCP; CD46), and factor I (IF). However, incomplete penetrance of mutations in each of these genes is reported. This suggests that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The reported precipitating events predominantly cause endothelial injury. Discovery of these mutations has revealed important genotype-phenotype correlations. MCP-HUS has a better prognosis and a better outcome after transplantation than either CFH-HUS or IF-HUS.
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PMID:Atypical haemolytic uraemic syndrome. 1696 92

The proteasome inhibitor, bortezomib, has antimyeloma activity even in myeloma cells refractory to multiple prior treatments. The most commonly reported adverse events in patients receiving bortezomib are sensory neuropathy, thrombocytopenia and gastrointestinal events. We report a patient with myeloma who developed pseudomembranous colitis after bortezomib treatment. Bortezomib has the boronic acid moiety which improves the specificity of proteasome inhibition and can be used as non-beta-lactam-based beta-lactamase inhibitors. This case indicates that gastrointestinal toxicities by bortezomib may be caused, in part, as a result of change in the colonization of colonic microflora.
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PMID:Pseudomembranous colitis following bortezomib therapy in a myeloma patient. 1723 15

Hemolytic uremic syndrome is the clinical triad of thrombocytopenia, microangiopathic hemolytic anaemia and acute renal failure. Cases not associated with a preceding Shiga-like toxin producing Escherichia coli are described as atypical HUS (aHUS). Approximately 50% of patients with aHUS have mutations in one of three complement regulatory proteins, Factor H (CFH), membrane cofactor protein (MCP;CD46) or factor I (IF). A common feature of these three proteins is that they regulate complement by cofactor activity. Decay accelerating factor (DAF; CD55) regulates the complement system by disassociating the alternative and classical pathway convertases. Like CFH and MCP, the gene for DAF lies within the regulators of complement activation (RCA) gene cluster at 1q32. In 1998, we described linkage to this region in families with aHUS which led to the discovery of mutations in CFH and MCP. We therefore genotyped DAF in a panel of 46 aHUS patients including families with linkage to the RCA cluster. A mutation, I197V, was identified in one patient with familial HUS which was not found in 100 healthy controls. Molecular modelling of this mutation shows that the I197V mutation does not reside in an area which would be predicted to be important in decay accelerating activity. The expression of I197V on EBV-transformed B lymphocytes was equivalent to that of wild type controls. There was no significant decrease in decay acceleration activity of the recombinantly produced I197V mutant compared with wild type, as measured by a complement-mediated lytic assay. In conclusion, this study, identifies only one mutation in DAF in 46 patients with aHUS. This mutation, I197V, does not impair complement regulation and cannot be implicated in the pathogenesis of aHUS in this patient. This suggests that the complement regulatory abnormality in aHUS is principally one of deficient cofactor activity rather than of decay acceleration activity.
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PMID:The decay accelerating factor mutation I197V found in hemolytic uraemic syndrome does not impair complement regulation. 1736 71


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