Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have demonstrated that primary interleukin 13 (IL-13) binding protein IL-13 receptor (IL-13R) alpha chain plays an important role in IL-13 binding and internalization in the IL-13R system. Although IL-13R alpha chain is expressed on many cancer cell lines, some cancer types do not express or express low levels of this receptor chain. Consequently, these cells show no or low sensitivity to the cytotoxic effect of a recombinant chimeric protein composed of IL-13 and a mutated form of a Pseudomonas exotoxin, IL13-PE38QQR. Here we demonstrate that pancreatic cancer, renal cell carcinoma, head and neck cancer, and glioblastoma cell lines that were genetically altered to express high levels of IL-13R alpha chain increase their binding affinity for IL-13, and increase their sensitivity to IL13-PE38QQR by at least 6-fold to 1000-fold compared with mock-transfected control cells. This observation was made by protein synthesis inhibition assay and confirmed by clonogenic assay. Our studies provide a proof of principle for a novel strategy for cancer therapy that combines gene transfer and targeted cytotoxin therapy.
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PMID:Sensitization of cancer cells to interleukin 13-pseudomonas exotoxin-induced cell death by gene transfer of interleukin 13 receptor alpha chain. 1098 56

Surgery, radiotherapy and chemotherapy have minimally altered survival of glioblastoma patients. We explored a specific approach for glioblastoma therapy in which cellular interleukin-13 (IL-13) receptors were targeted by an IL-13 cytotoxin. A wide array of human glioblastoma cell lines expressing the receptor for IL-13 were effectively killed by an IL-13 cytotoxin, a chimeric protein composed of human IL-13 and a mutated form of Pseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin). Daily (qd) intratumoral injections of IL-13 toxin (50 and 100 microg/kg/day) for 5 consecutive days into subcutaneous human U251 glioblastoma tumors (approx. 30 mm(2)) in nude mice resulted in complete regression of tumors in 4/5 and 5/5 mice, respectively. Tumor regression persisted for at least 221 days postimplantation. Three alternate day injections (qod) of IL-13 toxin (250 microg/kg/day) into other subcutaneous U87 glioblastoma tumors also produced durable complete responses (CR) in all 5 mice. Twice daily (bid) intraperitoneal injections of IL-13 toxin at 25 or 50 microg/kg/dose for 5 days (total doses = 10) regressed U251 tumors by 45% and 58% with 1/5 and 2/5 CRs, respectively, on day 54. Intraperitoneal administration of IL-13 toxin with an identical schedule at a dose of 50 microg/kg injected into mice bearing U87 xenografts reduced tumor burden by one-half on day 36. Similar doses (25 or 50 microg/kg) with a daily schedule (qd x 5) by the intravenous route also suppressed growth of U251 subcutaneous tumors by 75% and 81% with 1/6 CR in either group by day 34. All mice tolerated therapy well without any visible signs of toxicity. On the basis of these studies, we have initiated a Phase I clinical trial using IL13-PE38QQR in patients with recurrent glioblastoma. Published 2001 Wiley-Liss, Inc.
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PMID:Interleukin-13 receptor as a unique target for anti-glioblastoma therapy. 1129 Oct 41

The interleukin-13 receptor (IL-13R) complex is composed of 2 different chains, IL-13Ralpha1 (also known as IL-13Ralpha') and IL-13Ralpha2 (also known as IL-13Ralpha). For a functional IL-13 receptor, the IL-13Ralpha1 chain forms a productive complex with the primary IL-4 binding protein (IL-4Ralpha also known as IL-4Rbeta). However, the function of the IL-13Ralpha2 chain is not clear even though this chain binds IL-13 with high affinity. This study demonstrates that IL-13Ralpha2 can undergo internalization after binding to ligand without causing activation of its signaling pathways. These conclusions were drawn on the basis of (1) internalization of (125)I-IL-13 in Chinese hamster ovarian (CHO-K1) and T98G glioblastoma cells transiently transfected with the IL-13Ralpha2 chain; (2) a recombinant chimeric fusion protein comprising IL-13 and a mutated form of Pseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin) is specifically cytotoxic to IL-13Ralpha2-transfected CHO-K1 cells in a gene dose-dependent manner, whereas cells transfected with vector alone were not sensitive; and (3) IL-13 did not cause activation of signal transduction and activation of transcription 6 (STAT6) in IL-13Ralpha2-transfected cells. IL-13 efficiently caused activation of STAT6 protein in cells transfected with the IL-13Ralpha1 and IL-4Ralpha chains, and IL-13Ralpha2 inhibited this activation. Taken together, these observations indicate that internalization of IL-13Ralpha2 is signal independent and that this property of IL-13Ralpha2 can be exploited for receptor-directed cancer therapy.
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PMID:The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. 1131 57

NeoPharm, under license from the NIH and the FDA, is developing a chimeric human IL-13 fused in frame to a genetically engineered truncated Pseudomonas exotoxin (PE38QQR) molecule, for its potential as an antitumor agent [266296], [281418], [290480]. NeoPharm filed an IND in 1999 for renal cell carcinoma (RCC) and glioma [319690], [325001]; an additional IND was filed in March 2000 for the treatment of glioblastoma. In December 2000, NeoPharm initiated phase I/II trials of IL-13-PE38QQR involving patients with refractory glioblastoma multiforme. This trial was being conducted by the New Approaches to Brain Tumor Therapy, a research consortium sponsored by the NCI. At that time, the first patient with brain cancer had completed treatment with IL-13-PE38QQR [393197]. In October 1999, NeoPharm initiated phase I trials of hIL-13-PE38QQR for the treatment of patients with RCC [343878]. In February 2000, Dirks & Co estimated the potential US market for hIL-13-PE38QQR to be $5.8 billion [414515].
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PMID:hIL-13-PE38QQR. NeoPharm. 1171 20

Interleukin (IL)-4 and IL-13 share the type II IL-4 receptor for cell signaling. We show that despite expressing the necessary signaling components, glioblastoma cells failed to respond to either IL-4 or IL-13. This was in part because of the expression of a high-affinity IL-13-binding transmembrane protein IL-13R(alpha)2 that inhibited IL-13-mediated Stat6 activation by acting as a decoy receptor. In contrast, normal human astrocytes that did not express the IL-13R(alpha)2 gene efficiently induced Stat6 activation in response to both IL-4 and IL-13. Transient expression of the IL-13R(alpha)2 transgene in nonexpressing heterologous cells inhibited not only IL-13- but also IL-4-mediated signal transduction and Stat6-responsive gene expression. The inhibition was likely mediated through the physical interaction between the short intracellular domain of the IL-13R(alpha)2 protein and the cytoplasmic domain of the IL-4R(alpha) chain that harbors the Stat6 docking sites. Thus, IL-13R(alpha)2 acts as an inhibitor of IL-4-dependent signal transduction pathways via a novel mechanism that is independent of ligand binding.
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PMID:IL-13R(alpha)2, a decoy receptor for IL-13 acts as an inhibitor of IL-4-dependent signal transduction in glioblastoma cells. 1186 89

Fusion proteins composed of tumor binding agents and potent catalytic toxins show promise for intracranial therapy of brain cancer and an advantage over systemic therapy. Glioblastoma multiforme (GBM) is the most common form of brain cancer and overexpresses IL-13R. Thus, we developed an interleukin-13 receptor targeting fusion protein, DT(390)IL13, composed of human interleukin-13 and the first 389 amino acids of diphtheria toxin. To measure its ability to inhibit GBM, DT(390)IL13 was tested in vitro and found to inhibit selectively the U373 MG GBM cell line with an IC(50) around 12 pmol/l. Cytotoxicity was neutralized by anti-human-interleukin-13 antibody, but not by control antibodies. In vivo, small U373 MG glioblastoma xenografts in nude mice completely regressed in most animals after five intratumoral injections of 1 microg of DT(390)IL13 q.o.d., but not by the control fusion protein DT(390)IL-2. DT(390)IL13 was also tested against primary explant GBM cells of a patient's excised tumor and the IC(50) was similar to that measured for U373 MG. Further studies showed a therapeutic window for DT(390)IL13 of 1-30 microg/injection and histology studies and enzyme measurements showed that the maximum tolerated dose of DT(390)IL13 had little effect on kidney, liver, spleen, lung and heart in non-tumor-bearing immunocompetent mice. Together, these data suggest that DT(390)IL13 may provide an important, alternative therapy for brain cancer.
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PMID:Targeting glioblastoma multiforme with an IL-13/diphtheria toxin fusion protein in vitro and in vivo in nude mice. 1203 62

The interleukin 13 alpha 2 receptor (IL-13Ralpha2) is highly expressed in human glioma cells. As a consequence this receptor has been proposed as a potential target for immunotherapeutic approaches for treating brain tumors. In developing animal models that may utilize the IL-13Ralpha2 receptor as an immunotherapeutic target, only the murine gene sequence has thus far been elucidated. The purpose of the present study, therefore, was to determine the gene sequence and tissue distribution of IL-13Ralpha2 in the rat. A search of the NCBI expressed sequence tag (EST) database with human and mouse IL-13Ralpha2 gene sequences identified a rat EST with high homology to the human and mouse IL-13Ralpha2 conserved region. Based on the sequence information, a 1917 bp rat IL-13Ralpha2 cDNA was cloned using the 5' and 3' RACE PCR technique. The cloned rat IL-13Ralpha2 cDNA contains a full-length 1158 bp open reading frame. The deduced protein is 91.2% and 54.2% homologous to mouse and human IL- 13Ralpha2, respectively, at the amino acid level. Analysis shows that the rat IL-13Ralpha2 is structurally conserved and similar to human and mouse. It has a very short cytoplasmic domain, an extracellular domain containing an N-terminal fibronectin type III domain, four putative N-glycosylation sites, and a growth factor and cytokine receptor family motif WSEWS. Using RT-PCR techniques, the mRNA of rat IL-13Ralpha2 was detected in rat brain, spleen, liver, thymus, stomach, testis, and three rat glioblastoma cell lines C6, A15A5 and 9L. The cloning of rat IL-13Ralpha2 may be helpful to establish a rat model for IL-13Ralpha2 related glioma therapies.
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PMID:Molecular cloning of the rat IL-13 alpha 2 receptor cDNA and its expression in rat tissues. 1224 Nov 13

Apoptosis is not only essential for homeostasis in normal cells but also in cancer cells, in which it is associated with cell death mechanisms caused by novel therapeutics. We have previously reported that interleukin-13 receptors (IL-13R) are constitutively overexpressed on a majority of human malignant glioma cell lines and primary cell cultures. In addition, we have reported that IL-13 cytotoxin, comprised of human IL-13 and a mutated form of Pseudomonas exotoxin, is highly and specifically cytotoxic to these cells and can lead to pronounced antitumor activity in malignant glioma tumors in animal models. However, the molecular mechanisms of tumor cytotoxicity induced by IL-13 cytotoxin are poorly understood. In this study, we demonstrate that glioma tumors undergo apoptotic cell death on intratumoral administration of IL-13 cytotoxin. This conclusion was made based on (a) time-dependent induction of several proapoptotic molecules, such as caspases (caspase-3, -8, and -9) in tumors; (b) cleavage of procaspase-3 and poly(ADP-ribose) polymerase (PARP); and (c) the release of cytochrome c from mitochondria to the cytosol on injection of IL-13 cytotoxin in U251 glioblastoma tumors established in immunodeficient animals. These indicators of two major pathways of apoptosis were detected in tumors even though IL-13 cytotoxin was no longer present in tumors. In addition, we found that inducible nitric oxide was expressed in tumors in a time-dependent manner with primary localization in infiltrating phagocytes after treatment with IL-13 cytotoxin. These studies demonstrate that IL-13 cytotoxin mediates apoptotic death of glioma cells, resulting in regression of established tumors. Our studies will help unravel the molecular pathways of cell death associated with tumor regression and provide additional insight and define apoptosis as possible surrogate marker of tumor response.
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PMID:Intratumor administration of interleukin 13 receptor-targeted cytotoxin induces apoptotic cell death in human malignant glioma tumor xenografts. 1248 22

The interleukin 13 alpha 2 receptor (IL-13Ra2) has been shown to be expressed in most malignant glioblastoma cells. Recent studies suggest that IL-13Ra2 serves as a dominant negative inhibitor or a decoy receptor for IL-13. To investigate the transcriptional regulation of this receptor, we cloned and characterized the promoter for the human IL-13Ra2 gene. Our results demonstrate that this promoter contains three TATA boxes and one CCAAT site. Several putative transcriptional factor binding sites for nuclear factor of activated T cells 1, AP1 (c-JUN and c-FOS), AP2, GABP, OCT1, GATA3, PRE, and C-ETS1 were predicted in the promoter region. Using the secreted alkaline phosphate reporter gene assay, we investigated the functional activity of the human IL-13Ra2 promoter by transient transfection in glioma cell lines U118, U87, and T98, which differ in their expression of the human IL-13Ra2 protein. The different secreted alkaline phosphate activities among these 3 cell lines suggest that the expression of human IL-13Ra2 is regulated at the transcriptional level. Methylation analysis showed that expression of IL-13Ra2 may not be the result of methylation of the CpG dinucleotides in the promoter region of the gene. Deletion analysis identified a 64 base pair (bp) region that is necessary for human IL-13Ra2 promoter activity. This 64-bp sequence contains cis-elements for AP1, nuclear factor of activated T cells, and AP2. The possible role of AP1 in the regulation of human IL-13Ra2 promoter activity was suggested by in vitro mutagenesis and c-JUN N-terminal kinase inhibition analysis.
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PMID:Molecular cloning and identification of the human interleukin 13 alpha 2 receptor (IL-13Ra2) promoter. 1281 24

A bispecific immunotoxin (IT) called DTAT13 was synthesized in order to target simultaneously the urokinase-type plasminogen activator receptor (uPAR)-expressing tumor neovasculature and IL-13 receptor expressing glioblastoma cells with the goal of intratumoral administration for brain tumors. The recombinant hybrid was created using the non-internalizing N-terminal fragment (ATF) of uPA and the IL-13 molecule for binding plus the catalytic and translocation portion of diphtheria toxin (DT) for killing. The 71 kDa protein was highly selective for human glioblastoma in vitro showing no loss on binding compared with DTAT and DTIL13 controls. In vivo, DTAT13 caused the regression of small tumors when administered at 10 micro g/day given on a five-dose schedule every other day. DTAT13 was able to target both overexpressed uPAR and the vasculature, as demonstrated by its ability to kill HUVEC cells. Also, mortality studies indicated that DTAT13 was less toxic than DTAT or DTIL13. These findings indicate that bispecific IT may allow treatment of a broader subset of antigenically diverse patients while simultaneously reducing the exposure to toxin required than if two separate agents were employed.
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PMID:A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model. 1504 12


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