Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iodine-131 tositumomab [B1, Bexxar , iodine-131 anti-B1 antibody] is a murine antibody conjugated to iodine 131 that recognises and binds to the B1 (CD20) antigen which is found specifically on B lymphocytes. Iodine-131 tositumomab has a dual mechanism of action. It is capable of initiating a host immune response to those B cells to which it is attached, and it also triggers apoptosis in a significant proportion of the cells to which it binds. The product was first discovered by Coulter Corporation, Miami, in collaboration with the Dana-Farber Cancer Institute and the University of Michigan. The spin-off company Coulter Pharmaceutical, upon its formation, obtained worldwide rights to iodine-131 tositumomab. (Coulter Corporation was acquired subsequently by Beckman Instruments in October 1997. The union of the two companies produced Beckman Coulter.) In December 2000, Coulter Pharmaceutical was acquired by, and merged into, Corixa Corporation.Iodine-131 tositumomab is available for licencing in Japan. Corixa Corporation and GlaxoSmithKline signed an agreement to jointly develop and commercialise iodine-131 tositumomab. The total agreement has a potential value of up to $US132 million, plus shared profits and royalties. The two companies will jointly market the antibody in the US following regulatory approval. Corixa Corporation has announced it expects iodine-131 tositumomab to be approved in the US for non-Hodgkin's lymphoma (NHL). Under the terms of the original agreement, GlaxoSmithKline will receive exclusive marketing rights outside the US, excluding Japan. However, an amended agreement between the two companies will allow Corixa Corporation to also market the product outside the US. In February 2003, the European Commission granted iodine-131 tositumomab orphan-drug designation. Corixa Corporation and GlaxoSmithKline also intend to jointly investigate the use of the product in other indications. GlaxoSmithKline may also receive access to second generation anti-CD20 compounds under its agreement with Corixa Corporation. In May 2003, Corixa Corporation entered into an agreement that will see GlaxoSmithKline market Bexxar in Canada. Under the terms of the agreement, Corixa Corporation will manufacture and supply the product to GlaxoSmithKline, who will register, market and sell it in Canada. In October 2001, Amersham PLC, a supplier of medical equipment, announced that its Amersham Health unit had signed a marketing agreement with Corixa Corporation. The agreement allows Amersham Health to market iodine-131 tositumomab in Europe. Corixa Corporation formed agreements with Boehringer Ingelheim Pharma KG and Lonza Biologics to produce the B1 antibody and radiolabelling of the antibody has been contracted out to MDS Nordion.Iodine-131 tositumomab has received orphan drug and fast track designation for the treatment of NHL. Corixa Corporation submitted a Biologics Licence Application (BLA) to the US FDA in 1999, seeking permission to market Bexxar in the US for the treatment of relapsed or refractory, low grade or transformed low grade B-cell NHL. Following a priority review, the US FDA requested that Corixa Corporation reformat certain sections and perform additional analyses of existing data in its BLA. Corixa Corporation and GlaxoSmithKline resubmitted their BLA to the US FDA in September 2000. The BLA was subsequently accepted by the US FDA in November 2000. However, in March 2001, the US FDA requested additional information in its complete review letter to Corixa Corporation and marketing partner GlaxoSmithKline. The two companies submitted data pertaining to the chemistry, manufacturing and controls section of the BLA, and to the majority of the questions regarding the clinical section of the BLA in August 2001. Corixa Corporation and GlaxoSmithKline submitted the remainder of the response to the US FDA in September 2001, following an independent review of clinical trial data. In March 2002, Corixa Corporation received another complete review letter from the US FDA, which stated that additional clinical trials would have to be conducted in order to provide adequate evidence of the safety and clinical benefit of Bexxa. The US FDA also denied Corixa Corporation's request for accelerated approval, stating that the data provided was inadequate to show that Bexxar filled an unmet medical need. Corixa Corporation has met formally with the US FDA but the two were unable to resolve their differences. Corixa Corporation will now file a formal request for dispute resolution under the Food and Drug Administration Modernisation Act. Corixa Corporation also requested a presentation of Bexxa data to the US FDA's scientific advisors. In June 2002, the US FDA granted the company's appeal for additional regulatory review. In December 2002, the US FDA's Oncologic Drugs Advisory Committee agreed that Bexxar has clinical benefit for patients with NHL. In May 2003, Corixa Corporation and GlaxoSmithKline announced that they had fulfilled many of the steps required for US FDA approval, however the US FDA has extended its review of the application for another 3 months. This extension will allow for further refinement of post marketing commitments and package insert language, and to ensure they are consistent with an updated safety database requested by the US FDA and submitted by Corixa Corporation in early April. GlaxoSmithKline was waiting for the outcome of the situation before deciding on marketing plans for Bexxar. Corixa Corporation and GlaxoSmithKline will conduct a head-to-head study of Bexxar and Idec's Zevalin, planned for mid-2003. The trial will likely be one of three phase IV studies that the US FDA requires for accelerated approval of Bexxar. Corixa Corporation initiated its Expanded Access Program for Bexxar in response to requests from physicians and patients for continued access to Bexxar during the period prior to potential US FDA marketing approval.A phase II multicentre trial of Bexxar in combination with CHOP chemotherapy is underway in the US as first-line therapy in patients with intermediate-grade NHL. Corixa Corporation has initiated a phase II trial of iodine-131 tositumomab in combination with cyclophosphamide, vincristine and prednisone for the treatment of previously untreated low-grade NHL. The trial was initiated while the company was preparing its BLA for Bexxar for use as a single agent for relapsed or refractory NHL. Corixa Corporation intends to pursue additional trials to expand the potential use of iodine-131 tositumomab to other indications, including chronic lymphocytic leukaemia. The agent is also in a clinical trial for preparation in autologous bone marrow transplant patients. The trial is designed to test the combination of iodine-131 tositumomab and chemotherapy. The trial began in 1995 and has so far enrolled 40 patients. In addition, a phase II dose-escalation trial has begun at the University of Nebraska for the combined use of iodine-131 tositumomab and chemotherapy as preparation for autologous bone marrow transplant. Corixa Corporation has received an issued US patent covering methods for administering and dosing radioimmunotherapy for the treatment of B-cell lymphomas. The patent covers iodine-131 tositumomab and other anti-CD20 antibodies used to aid in selective tumour targeting. Corixa Corporation has exclusive rights to the patent.A February 2000 media release from GlaxoSmithKline and Corixa Corporation stated that they had been issued a composition patent relating to radiolabelled monoclonal antibodies (including Bexxar) for the treatment of B-cell lymphomas. On 11 September 2001, IDEC announced that it had filed two separate lawsuits. The first lawsuit is against Corixa Corporation and the University of Michigan on six patents pertaining to products and processes related to radioimmunotherapy. They seek a declaration that Zevalin does not infringe Corixa Corporation's issued US patents. The second lawsuit involves two patents relating to cell culture media, and is against GlaxoSmithKline. IDEC's lawsuit in this case, seeks a declaration that its manufacture of Zevalin does not infringe GlaxoSmithKline's issued US patents. Corixa Corporation and GlaxoSmithKline have also filed a complaint for patent infringement against IDEC. These actions however, should have no effect on the regulatory process that Zevalin is completing, or prevent IDEC from launching the drug before iodine-131 tositumomab.A year earlier, in March 2001, the Financial Times reported that Bexxar could reach peak sales of $US120 million. In 1998, Coulter Pharmaceutical received a licencee fee payment of $US34 million from SmithKline Beecham (now GSK) in the fourth quarter of the year, as part of the joint development and commercialisation agreement for Bexxar.
 ...
PMID:Iodine-131 Tositumomab: (131)I-anti-B1 antibody, (131)I-tositumomab, anti-CD20 murine monoclonal antibody-I-131, B1, Bexxar, (131)I-anti-B1 antibody, iodine-131 tositumomab, iodine-131 anti-B1 antibody, tositumomab. 1289 47

Aberrant accumulation of beta-catenin protein because of mutation of either the beta-catenin or adenomatous polyposis coli gene plays an essential role in the development of colorectal carcinoma. We established previously a stable clone of the rat small intestinal epithelial cell line IEC6, which is capable of inducing stabilized beta-catenin protein lacking NH(2)-terminal glycogen synthase kinase-3beta phosphorylation site under a strict control of the tetracycline-regulatory system. This clone, IEC6-TetOFF-beta-catenin DeltaN89, shows in vitro polypoid growth on the removal of doxycycline and seems to be an appropriate model for analyzing the molecular mechanisms of early intestinal carcinogenesis. Of >2000 protein spots displayed by newly developed two-dimensional difference gel electrophoresis, 22 were found to be up- or down-regulated on the induction of stabilized beta-catenin. The majority of these proteins fell into two categories: (a) redox-status regulatory proteins and (b) cytoskeleton-associated proteins. Representatively, a key redox-status regulatory protein, manganese superoxide dismutase, up-regulated in IEC6 cells expressing stabilized beta-catenin protein, was overexpressed in adenoma and adenocarcinoma cells of familial adenomatous polyposis patients in parallel with the accumulation of beta-catenin. These results suggest that aberrant accumulation of beta-catenin might contribute to colorectal carcinogenesis by affecting redox status in the mitochondria of intestinal epithelial cells.
Cancer Res 2003 Aug 01
PMID:Proteomic analysis of intestinal epithelial cells expressing stabilized beta-catenin. 1290 44

This work examined the effect of chorionic gonadotropin on proliferative and morphogenetic reactions in the uterus under short- and long-term estrogen treatments. Ovariectomized mice received a single injection with estradiol dipropionate (2 micro g per 100 g; subcutaneously, sc) or vehicle and injections with human chorionic gonadotropin (10 IU per 100 g; sc) or vehicle twice a day for 2 days. Other groups of animals received injections with estradiol once a week or vehicle and injections with chorionic gonadotropin or vehicle once a day for 30 days. The uteri were removed 48 h after the last estradiol or vehicle injection. In animals treated with estradiol and chorionic gonadotropin for a month, the incidence of atypical endometrial hyperplasia was significantly higher. In animals treated with estradiol and chorionic gonadotropin for 2 days or for a month, uterine mass was slightly increased, the number of mitotic cells and BrdU-labeled cells was greater in luminal epithelium, glandular epithelium, stromal and myometrial cells, whereas the expression of estrogen receptors-alpha was lower in all uterine compartments, than in control. In mice who received estradiol and chorionic gonadotropin for 2 days, levels of beta-catenin and glycogen synthase kinase-3beta in luminal and glandular epithelia were lower. In animals treated with estradiol and chorionic gonadotropin for a month, the level of beta-catenin was slightly higher, and the expression of glycogen synthase kinase-3beta was lower in luminal and glandular epithelia. Thus, chorionic gonadotropin exerts estradiol-induced proliferative and morphogenetic changes in the uterus. This action of chorionic gonadotropin is associated with decreased expression of estrogen receptors-alpha and with changes in expression of beta-catenin and glycogen synthase kinase-3beta in the uterus.
Int J Gynecol Cancer
PMID:Uterine response to estradiol under action of chorionic gonadotropin in mice. 1291 26

To identify novel regulators of Wnt signaling, we performed yeast two-hybrid analyses with Dvl-1 and identified BP75 as a candidate. Here, we demonstrated that BP75 directly interacts with Dvl-1 in mammalian cells and enhances TCF-dependent gene expression induced by Dvl-1. In support of these results, BP75 in cooperation with Dvl-1 was found to facilitate dephosphorylation at Tyr216 of glycogen synthase kinase-3beta and consequently inhibit its kinase activity. Furthermore, the nuclear translocation and formation of vesicular structures of beta-catenin were induced by BP75 and Dvl-1 in a synergistic manner. Collectively, these results provided us a novel mechanism in Wnt signaling where BP75 plays important regulatory roles between glycogen synthase kinase-3beta and Dvl.
Cancer Res 2003 Aug 15
PMID:BP75, bromodomain-containing M(r) 75,000 protein, binds dishevelled-1 and enhances Wnt signaling by inactivating glycogen synthase kinase-3 beta. 1294 96

The aim of this study is to investigate the potential correlation between the expression of phosphorylated glycogen synthase kinase-3beta (phospho-GSK-3beta) and beta-catenin, and the mutations of beta-catenin gene at the consensus GSK-3beta phosphorylation site. The reason for this approach is to gain a better understanding of the molecular mechanisms of hepatocarcinogenesis in Malaysia. The expression of phospho-GSK-3beta and beta-catenin by immunohistochemistry and the mutations of beta-catenin were studied in 23 hepatocellular carcinoma (HCC) and surrounding tissues. Overexpression of phospho-GSK-3beta and beta-catenin was found in 12/23 (52.2%) and 13/23 (56.5%) in HCC tissues, 6/23 (26.1%) and 9/23 (39.1%) in surrounding tissues, respectively. Overexpression of beta-catenin in HCC tissues compared to the surrounding liver tissue was found to be higher in HCC tissues (p=0.015). In addition, we found that the expression of phospho-GSK-3beta was related with the accumulation of beta-catenin in surrounding tissues (p<0.05). The expression of phospho-GSK-3beta and its association with the development of HCC is reported for the first time. In addition, this is the first report from Malaysia which shows that there are no mutations at the GSK-3beta consensus phosphorylation sites on beta-catenin gene in all 23 paired HCC and surrounding tissues. This result differed from HCC in geographical areas with high aflatoxin exposure.
Cancer Lett 2003 Sep 25
PMID:GSK-3beta phosphorylation and alteration of beta-catenin in hepatocellular carcinoma. 1296 93

The Met receptor tyrosine kinase has been shown to be overexpressed or mutated in a variety of solid tumors and has, therefore, been identified as a good candidate for molecularly targeted therapy. Activation of the Met tyrosine kinase by the TPR gene was originally described in vitro through carcinogen-induced rearrangement. The TPR-MET fusion protein contains constitutively elevated Met tyrosine kinase activity and constitutes an ideal model to study the transforming activity of the Met kinase. We found, when introduced into an interleukin 3-dependent cell line, TPR-MET induces factor independence and constitutive tyrosine phosphorylation of several cellular proteins. One major tyrosine phosphorylated protein was identified as the TPR-MET oncoprotein itself. Inhibition of the Met kinase activity by the novel small molecule drug SU11274 [(3Z)-N-(3-chlorophenyl)-3-([3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl]methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide] led to time- and dose-dependent reduced cell growth. The inhibitor did not affect other tyrosine kinase oncoproteins, including BCR-ABL, TEL-JAK2, TEL-PDGFbetaR, or TEL-ABL. The Met inhibitor induced G(1) cell cycle arrest and apoptosis with increased Annexin V staining and caspase 3 activity. The autophosphorylation of the Met kinase was reduced on sites that have been shown previously to be important for activation of pathways involved in cell growth and survival, especially the phosphatidylinositol-3'-kinase and the Ras pathway. In particular, we found that the inhibitor blocked phosphorylation of AKT, GSK-3beta, and the pro-apoptotic transcription factor FKHR. The characterization of SU11274 as an effective inhibitor of Met tyrosine kinase activity illustrates the potential of targeting for Met therapeutic use in cancers associated with activated forms of this kinase.
Cancer Res 2003 Sep 01
PMID:A novel small molecule met inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. 1450 Mar 82

GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr138 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors.
 ...
PMID:Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. 1452 25

Prostate cancer is a major health threat for American men. Therefore, the development of effective therapeutic options is an urgent issue for prostate cancer treatment. In this study, we evaluated the effect of glycogen synthase kinase-3beta (GSK-3beta) suppression on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human prostate cancer cell lines. In the presence of lithium chloride (LiCl) or SB216763, the GSK-3beta inhibitors, TRAIL-induced cell death was dramatically enhanced, and the enhanced cell death was an augmented apoptotic response evidenced by increased Annexin V labeling and caspase-3 activation. GSK-3beta gene silencing mediated by a small interference RNA (siRNA) duplex also sensitized the cells to TRAIL, confirming the specificity of GSK-3beta suppression. Importantly, TRAIL stimulation increased GSK-3beta tyrosine phosphorylation at Y216, suggesting that GSK-3beta is activated by TRAIL. Furthermore, TRAIL sensitization was associated with increased proteolytic procession of caspase-8 and its downstream target BID, and z-IETD-FMK, the inhibitor specific to active caspase-8 totally blocked LiCl-induced TRAIL sensitization. Finally, Trichodion, a potent nuclear factor-kappaB (NF-kappaB) inhibitor, could not affect LiCl-induced TRAIL sensitization, although GSK-3beta inhibitors significantly blocked TRAIL-reduced NF-kappaB activity in prostate cancer cells. These results indicate that GSK-3beta suppression sensitizes prostate cancer cells to TRAIL-induced apoptosis that is dependent on caspase-8 activities but independent of NF-kappaB activation, and suggest that a mechanism involving GSK-3beta activation may be responsible for TRAIL resistance in prostate cancer cells.
Mol Cancer Ther 2003 Nov
PMID:Glycogen synthase kinase-3beta suppression eliminates tumor necrosis factor-related apoptosis-inducing ligand resistance in prostate cancer. 1461 95

Glycogen synthase kinase-3 (GSK-3) has perplexed signal transduction researchers since its detection in skeletal muscle 25 years ago. The enzyme confounds most of the rules normally associated with protein kinases in that it exhibits significant activity, even in resting, unstimulated cells. However, the protein is highly regulated and potently inactivated in response to signals such as insulin and polypeptide growth factors. The enzyme also displays a distinct and unusual preference for substrates that have been previously phosphorylated by other protein kinases which provides obvious opportunities for cross-talk. Its substrates are diverse and are predominantly regulatory molecules. The molecular cloning of the kinase revealed it to be encoded by two related but distinct genes. Moreover, the mammalian proteins showed remarkable similarity to a fruitfly protein isolated on the basis of its role in cell fate determination. From these humble beginnings, study of the enzyme has accrued further surprises such as its inhibition by lithium, its regulation by serine and tyrosine phosphorylation and its implication in several human disorders including Alzheimers disease, bipolar disorder, cancer and diabetes. Most recently, small molecule inhibitors of GSK-3 have been developed and assessed for therapeutic potential in several of models of pathophysiology. The question is whether modulation of such an "involved" enzyme could lead to selective restoration of defects without multiple unwanted side effects. This review summarizes current knowledge of GSK-3 with respect to its known functions, together with an assessment of its real-life potential as a drug target for chronic conditions such as type 2 diabetes.
 ...
PMID:Physiological roles of glycogen synthase kinase-3: potential as a therapeutic target for diabetes and other disorders. 1468 59

EGF receptor (EGFR) overexpression correlates with metastasis in a variety of carcinomas, but the underlying mechanisms are poorly understood. We demonstrated that EGF disrupted cell-cell adhesion and caused epithelial-to-mesenchymal transition (EMT) in human tumor cells overexpressing EGFR, and also induced caveolin-dependent endocytosis of E-cadherin, a cell-cell adhesion protein. Chronic EGF treatment resulted in transcriptional downregulation of caveolin-1 and induction of the transcriptional repressor Snail, correlating with downregulation of E-cadherin expression. Caveolin-1 downregulation enhanced beta-catenin-TCF/LEF-1 transcriptional activity in a GSK-3beta-independent manner. Antisense RNA-mediated reduction of caveolin-1 expression in EGFR-overexpressing tumor cells recapitulated these EGF-induced effects and enhanced invasion into collagen gels. We propose that EGF-induced negative regulation of caveolin-1 plays a central role in the complex cellular changes leading to metastasis.
Cancer Cell 2003 Dec
PMID:Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. 1470 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>