Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the passive Heymann nephritis (PHN) model of membranous nephropathy, C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which is partially mediated via production of eicosanoids. Using rat GEC in culture, we demonstrated that sublytic C5b-9 induced tyrosine phosphorylation of the epidermal growth factor receptor (EGF-R), Neu, fibroblast growth factor receptor-2, and hepatocyte growth factor receptor. In addition, C5b-9 stimulated increases in tyrosine(204) phosphorylation of extracellular signal-regulated kinase-2 (ERK2), as well as free [(3)H]arachidonic acid (AA) and prostaglandin E(2) (PGE(2)). Phosphorylated EGF-R bound the adaptor protein, Grb2, and the EGF-R-selective tyrphostin, AG1478, blocked the C5b-9-induced ERK2 phosphorylation, [(3)H]AA release, and PGE(2) production by 45 to 65%, supporting a functional role for EGF-R kinase in mediating the activation of these pathways. Glomeruli isolated from rats with PHN demonstrated increases in ERK2 tyrosine(204) phosphorylation and PGE(2) production, as compared with glomeruli from control rats, and these increases were partially inhibited with AG1478. Thus, C5b-9 induces transactivation of receptor tyrosine kinases, in association with ERK2 activation, AA release, and PGE(2) production in cultured GEC and glomerulonephritis in vivo. Transactivated tyrosine kinases may serve as scaffolds for assembly and/or activation of proteins, which then lead to activation of the ERK2 cascade and AA metabolism.
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PMID:Complement C5b-9 induces receptor tyrosine kinase transactivation in glomerular epithelial cells. 1055 Mar 26

There is an urgent need for new therapies to treat non-small cell lung cancer (NSCLC) because current chemotherapy regimens are of limited effectiveness. The role of vascular endothelial growth factor in promoting tumor angiogenesis, in maintaining existing vasculature, and in resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (Avastin), a monoclonal antibody directed against vascular endothelial growth factor, has shown promise in treating a number of different cancers. In a recent Phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy significantly increased the time to progression and increased the response rate when compared with chemotherapy alone. This was particularly impressive in the subset of patients with non-squamous histology. Bevacizumab is generally well tolerated and did not appear to increase the incidence or severity of nausea/vomiting, neuropathy and renal toxicity, which are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in Phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related bleeding episodes (hemoptysis/hematemesis) seem to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor. Present ongoing studies are under way in NSCLC including (a) a Phase II neo-adjuvant study in combination with paclitaxel and carboplatin in patients with stage IB-IIA NSCLC; (b) a Phase I/II study of bevacizumab in combination with the epidermal growth factor receptor tyrosine kinase inhibitor agent, Tarceva, in patients with previously treated NSCLC; and (c) an Eastern Cooperative Group randomized Phase III study of paclitaxel and carboplatin with/without bevacizumab in patients with previously untreated IIIB (malignant pleural effusion) or metastatic NSCLC. These studies will help to establish the role of bevacizumab in NSCLC.
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PMID:Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. 1521 70

A simple and quick protocol for chemical treatment, enzymatic digestion, and subsequent identification of proteins on ProteinChip arrays is presented. Chicken ovalbumin, bovine fetuin and a heavily posttranslationally modified protein, human epidermal growth factor receptor extracellular domain, were employed as model proteins to evaluate the novel protocol. The chemical treatment includes denaturation, reduction, and alkylation, while enzymatic digestion encompasses deglycosylation, dephosphorylation, and digestion by various proteases. All reactions were carried out on-chip in a sequential fashion. Peptide mass fingerprinting identified several peptides derived from the three proteins. This protocol was also applied to the analysis of urinary proteins from a male rat with puromycin-induced proteinuria. alpha-2u-Globulin, the major urinary protein in the normal male rat and albumin, the most abundant in the treated animal, were readily identified. This procedure demonstrates that complete on-chip treatment can be used for rapid protein identification and structural characterization.
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PMID:Complete chemical and enzymatic treatment of phosphorylated and glycosylated proteins on ProteinChip arrays. 1592

Angiotensin II (Ang II) has been implicated in the development of cardiovascular disorders and chronic kidney disease (CKD). Ang II causes renal lesions through the activation of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE, also called a disintegrin and a metalloproteinase domain 17) and the release of transforming growth factor (TGF)-alpha, which binds to and activates the epidermal growth factor receptor. Renal lesions such as glomerulosclerosis, tubular atrophy, fibrosis, mononuclear cell infiltration and proteinuria following chronic Ang II infusion are substantially reduced in mice lacking TGF-alpha and those given a specific TACE inhibitor. These findings indicate that the selective inhibition of renal TACE could have therapeutic potential in the treatment of CKD.
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PMID:TACE-dependent EGF receptor activation in angiotensin-II-induced kidney disease. 1660 Mar 87

Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Erlotinib HCl is a reversible, highly selective epidermal growth factor receptor tyrosine kinase inhibitor. Additionally, both agents have shown benefit in patients with previously treated non-small cell lung cancer (NSCLC). Preclinical data in xenograft models produced greater growth inhibition with the combination than with either agent alone. A phase I/II study in two centers examined combined erlotinib and bevacizumab treatment in patients with nonsquamous stage IIIB/IV NSCLC with one or more prior chemotherapy. In phase I, 150 mg/d erlotinib orally plus 15 mg/kg bevacizumab i.v. every 21 days was established as the phase II dose. A total of 40 patients were enrolled and treated in this study (34 patients at phase II dose): 21 were female, 30 had adenocarcinoma histology, 9 were never smokers, and 22 had two or more prior regimens. The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between erlotinib and bevacizumab. Eight patients (20.0%) had partial responses and 26 (65.0%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Encouraging antitumor activity and safety of erlotinib plus bevacizumab support further development of this combination for patients with advanced NSCLC. A randomized phase II trial has been completed, and a phase III trial is ongoing.
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PMID:Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. 1685 21

Preeclampsia is a pregnancy specific disorder characterised by hypertension and proteinuria occurring after the twentieth week of gestation. Preeclampsia induced hypertension is the result of increased vascular reactivity and endothelial dysfunction, however, the mechanisms underlying this state remain elusive. One possible mediator may be the matrix metalloproteinases (MMPs), a family of proteinases typically recognized for long term tissue remodelling. This review examines the evidence suggesting a role for MMPs in acutely regulating vascular function. Studies have shown that MMPs can activate vasoconstrictors (e.g. endothelin), inactivate vasodilators (e.g. calcitonin gene related peptide) and transactivate cell surface receptors responsible for vasoconstriction (e.g. epidermal growth factor receptor). The potential role of these proteinases in preeclampsia will then be discussed.
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PMID:Matrix metalloproteinases: control of vascular function and their potential role in preeclampsia. 1712 57

Angiogenesis and its role in the growth and development of metastases has become a topic of increasing importance. In non-small cell lung cancer (NSCLC), vascular endothelial growth factor (VEGF) plays an important role in angiogenesis, growth of the primary tumor, and development of metastases. In addition, elevated expression in tissue samples is a negative prognostic feature. For these reasons, VEGF is a worthy target for novel therapies. Recent clinical trials have shown that the anti-VEGF monoclonal antibody bevacizumab adds to the effect of chemotherapy in the metastatic setting. Hypertension and proteinuria are, as expected, commonly seen in this patient population, but the unexpected toxicity of life-threatening hemoptysis has also been observed. This makes careful patient selection especially important for this class of drugs. Our understanding of the VEGF pathway is increasing, as are the number of available targeted agents. In addition to the monoclonal antibody, bevacizumab, VEGF receptor tyrosine kinase inhibitors, multitargeted kinase inhibitors, and combination VEGF and epidermal growth factor receptor (EGFR) inhibition, are all being evaluated in NSCLC. Small phase I and II trials have suggested modest benefit when used alone; however, we now know that the anti-angiogenic therapies work best in combination with chemotherapy. The results of ongoing trials using these agents in combination with standard therapy will provide more insight into their potential benefit. As it is known that small tumors require angiogenesis to grow and metastasize, the use of anti-angiogenic therapies in the adjuvant setting may provide even greater benefit, and increase the potential cure rate in this population of patients. The results of well-designed phase III trials will be required to truly understand how to best use this class of targeted therapies in resectable and metastatic NSCLC.
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PMID:Inhibition of angiogenesis in the treatment of non-small cell lung cancer. 1789 8

Lung cancer is the leading cause of cancer-related death worldwide. Despite several chemotherapeutic agents, a survival plateau has been reached, so new treatment strategies are clearly needed. A strong interest is now focused on the use of targeted therapies for the management of non-small-cell lung cancer. Monoclonal antibodies against the epidermal growth factor receptor (EGFR; cetuximab) or vascular endothelial growth factor receptor (VEGFR; bevacizumab) and EGFR tyrosine kinase inhibitors (gefitinib, erlotinib) are generally well tolerated and do not have the severe systemic side effects usually seen with cytotoxic drugs. A considerable number of treated patients develop dermatologic side effects, such as acneiform eruption, xerosis, and eczema, and unfortunately, this is often one cause of negative impact on a patient's quality of life. No controlled clinical trials have been performed to manage rash, so it is necessary to provide suggestions for managing this frequent side effect. The main problems related to the class of angiogenesis inhibitors affecting VEGFRs are the exclusion of patients with brain metastases and/or squamous histology, and vascular adverse effects, such as hypertension, proteinuria, thrombosis, and hemorrhage. There are other new agents in clinical development, such as sorafenib, sunitinib, vorinostat, vandetanib, everolimus, panobinostat, and ASA404. They are all associated with a spectrum of toxicities, often reversible with interruption of dosing. Further research is required to clarify the role of targeted therapies and toxicities management.
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PMID:Toxicity of targeted therapy in non-small-cell lung cancer management. 1928 69

Several novel therapies have been approved recently in advanced renal cell carcinoma (RCC). These agents inhibit pathways downstream of loss of the von Hippel-Lindau gene VHL. They target the vascular endothelial growth factor (VEGF) ligand, VEGF receptor (VEGFR), mammalian target of rapamycin (mTOR), and other potentially important pathways. Even with improvements in survival, disease progresses in all patients. There is a critical need to increase complete responses (now rare). One such strategy is combining several agents to block different levels of the VEGF-VEGFR axis (vertical blockade). Alternatively, combination of a VEGF-VEGFR inhibitor with an mTOR inhibitor is attractive. Finally, horizontal blockade of VEGFR with epidermal growth factor receptor and/or platelet-derived growth factor receptor, all signaling pathways activated by hypoxia-inducible factor, is another approach. Already trials have revealed difficulties with combination therapy. By combining agents, the toxicity of 1 or both can be enhanced. The authors of this article report their experience with sorafenib plus bevacizumab, which produced increases in hand-foot syndrome, hypertension, and proteinuria, all known toxic effects. Clinical activity was impressive with 25 responses in 48 patients (52% response rate). Other combinations also required dose reductions (sorafenib with temsirolimus) or were intolerable (sunitinib with temsirolimus or sunitinib with bevacizumab). Unexpected toxicity characterized by microangiopathic hemolytic anemia occurred late in treatment with sunitinib and bevacizumab. Toxicity may be more severe in patients with RCC, who frequently have 1 kidney and poor renal function. Once tolerability for combination regimens has been established, it will be critical to design informative phase 2 trials and address the benefit of combination versus sequential therapy.
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PMID:Combination targeted therapy in advanced renal cell carcinoma. 1940 58

It is now clearly established that anti-vascular endothelial growth factor (VEGF) drug class induces hypertension and proteinuria sometimes related to thrombotic microangiopathy and/or various glomerulopathies, according to capillary and glomerular VEGF and VEGF-receptor expressions. As reported in the literature, anti-epidermal growth factor receptor (EGFR) therapies seem to be less nephrotoxic. Indeed, many reports of anti-EGFR nephrotoxicity are tubular dependent such as acute tubular necrosis, electrolyte disorders (hypophosphatemia, hypomagnesemia, etc.) or both. This is explained by elective tubular expression of renal EGF/EGFR. In this paper, we focus on electrolyte disorders related to anti-EGFR treatment and discuss the tubular involvement of these drugs based on their renal expression.
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PMID:Electrolyte disorders related to EGFR-targeting drugs. 1940 15


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