UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytotoxins directed to interleukin-4 receptors have shown to mediate relatively selective cytotoxicity against a variety of human cancer cells in vitro and in vivo. In an ongoing Phase I clinical trial, a recombinant protein comprised of circularly permuted IL-4 fused to a mutated form of Pseudomonas exotoxin (the fusion protein termed IL-4(38-37)-PE38KDEL or cpIL4-PE) has shown antitumour activity against malignant glioma. Human medulloblastomas are neuroectodermal tumours that occur in children and have a poor prognosis. The goal of this study was to determine whether human medulloblastoma derived cell lines express interleukin-4 receptor and whether interleukin-4 receptor expression is accompanied by sensitivity to cpIL4-PE. Medulloblastoma cell lines express interleukin-4 receptor at the protein and mRNA levels as determined by binding, indirect immunofluorescence and RT--PCR studies. These cells expressed IL-4Ralpha (also known as IL-4Rbeta) and IL-13Ralpha1 (also known as IL-13Ralpha') chains, however common gamma(c), a component of the interleukin-4 receptor system in immune cells was not detected. Consistent with the expression of IL-4R, cpIL4-PE was found to be highly and specifically cytotoxic to four of five medulloblastoma cell lines. Susceptibility of medulloblastoma cell lines to cpIL4-PE seemed to correlate closely to the functional IL-4 binding sites in general as demonstrated by 125I-IL-4 binding, but did not seem to correlate with mRNA or cell surface immunoreactive receptor protein expression. The sensitivity of medulloblastoma cells to cpIL4-PE could be eliminated by concurrent incubation with IL-4 or IL-13, but not with IL-2. None of these cell lines showed any change in proliferation upon treatment with exogenous IL-4. These studies establish the interleukin-4 receptor as a medulloblastoma-associated target for possible tumour-directed cancer therapy. Further studies are warranted to investigate interleukin-4 receptor expression in primary medulloblastoma tumours and sensitivity to cpIL-4PE in vitro and in vivo.
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PMID:IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein. 1187 May 21

We have previously demonstrated that human brain tumor cells, in particular glioblastoma multiforme (GBM), express abundant receptors for interleukin-13 on the cell surface. These receptors are composed of IL-13 receptor (IL-13R)alpha1, IL-13Ralpha2, and IL-4Ralpha chains. The significance of overexpression of IL-13R on tumor cells is not known. Because expression of IL-13R on glioma cells is an unexpected phenomenon, we examined whether these receptors are polymorphic. Therefore, we analyzed cDNA for IL-13Ralpha1 and IL-13Ralpha2 chain genes by PCR-based single-strand conformation polymorphism and direct sequencing techniques for a possible polymorphism in 19 GBM, one normal human astrocyte, and two fibroblast cell lines. All analyzed samples except normal astrocytes overexpressed IL-13Ralpha2; however, none of these cell lines showed a mutation in cDNA for IL-13Ralpha2 chain. In contrast, all GBM samples, normal astrocytes, and fibroblasts expressed mRNA for IL-13Ralpha1 with apparent single nucleotide polymorphism in the transmembrane domain. To study the function of IL-13R on brain tumor cells, we investigated the regulation of adhesion molecules by IL-13 as assessed by flow cytometric analysis. A172 cell line expressed a low level of vascular cell adhesion molecule-1 (VCAM-1), while U251 and LA1-5g cell lines expressed intercellular adhesion molecule-1 (ICAM-1). On the other hand E-selectin was not expressed in any cell lines. Interestingly, IL-13 increased the expression level of VCAM-1 in A172 cell line in a dose- and time-dependent manner. However, IL-13 did not modulate any other adhesion molecules. These results suggest that IL-13R on GBM cells are not rearranged but appear to be functional.
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PMID:Mutation and functional analysis of IL-13 receptors in human malignant glioma cells. 1193 9

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

In the first stage of engineering a herpes simplex virus (HSV)-1 that specifically targets human malignant glioma cells, we constructed a recombinant virus designated R5111 in which we have ablated the binding sites for sulfated proteoglycans in glycoproteins B and C, replaced the amino-terminal 148 aa in glycoprotein C by IL-13 flanked at its amino terminus with a signal peptide, and inserted a second copy of IL-13 after the amino acid 24 of glycoprotein D. In the process, the binding site for HveA, a viral entry receptor, was disrupted. We have also transformed a cell line (J1.1) lacking HSV-1 receptors to express IL13Ralpha2 receptor (J13R cells). We report the following: the R5111 recombinant virus replicates as well as wild-type virus in a variety of cell lines including cell lines derived from brain tumors. R5111 failed to replicate in the parent J1.1 cell line but multiplied to titers similar to those obtained in other cell lines in the J13R cell line. On the basis of the evidence that R5111 can use the IL13Ralpha2 receptor for entry, we conclude that HSV-1 can use receptors other than HveA or nectins, provided it can bind to them. The domains of gD that interact with HveA and nectin receptors are independent of each other. Lastly, the fusogenic activities of the glycoproteins in the viral envelope are not dependent on a set of unique interactions between glycoprotein D and its receptor. The construction of R5111 opens the way for construction of viruses totally dependent on selected receptors for entry or imaging of targeted cells.
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PMID:Engineered herpes simplex virus 1 is dependent on IL13Ralpha 2 receptor for cell entry and independent of glycoprotein D receptor interaction. 1241 44

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 restricted receptor for interleukin 13 (IL-13R alpha2) is over-expressed in high-grade astrocytoma (HGA), but not in normal organs. In order to design and examine new anti-HGA therapies, which are molecularly directed against IL-13R alpha2, we established an IL-13R alpha2-expressing syngeneic immunocompetent murine model of HGA. The model was obtained by transfecting G-26 murine glioma cells with IL-13R alpha2. G-26-IL-13R alpha2(+) cells, but not mock-transfected cells, became susceptible to IL-13 mutant-based cytotoxic proteins that kill human HGA cells. G-26-IL-13R alpha2(+) cells maintained their tumorigenicity in immunocompetent C57BL/J6 mice and preserved their expression of IL-13R alpha2 in vivo. These characteristics of the G-26-IL-13R alpha2(+) tumors allowed us to test molecularly defined anti-glioma passive immunotherapy. A targeted recombinant chimera cytotoxin composed of multiply mutated IL-13 (IL-13.E13Y/R66D/S69D) and a derivative of Pseudomonas exotoxin (PE), PE1E, IL-13.E13Y/R66D/S69D-PE1E, was used in anti-tumor experiments. G-26-IL-13R alpha2(+) cells were killed by IL-13.E13Y/R66D/S69D-PE1E in an IL-4-independent fashion. To test the cytotoxin in vivo, G-26-IL-13R alpha2(+) tumors were established in C57BL/J6 mice and when the tumors reached a size of at least 50 mm3, the mice were treated with IL-13.E13Y/R66D/S69D-PE1E. In the mice treated with the targeted fusion cytotoxin, the tumors regressed and 80% of the animals were cured. This study documents the establishment of an IL-13R alpha2-positive model of HGA in immunocompetent rodents. Furthermore, the effectiveness and safety of the targeted IL-13-based cytotoxin against IL-13R alpha2-expressing tumors in a more clinically relevant in vivo HGA model is promising with regard to the future clinical utility of the cytotoxin.
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PMID:Molecular targeting with recombinant cytotoxins of interleukin-13 receptor alpha2-expressing glioma. 1295 92

IL13PE38QQR is a recombinant toxin composed of the enzymatically-active portion of Pseudomonas Exotoxin A conjugated with human IL13. Binding of IL13-PE38 to the IL13 receptor (IL13R) permits internalization of the recombinant toxin resulting in selective and potent cytoxicity at nanomolar concentrations. Normal brain tissue expresses little or no IL13R, but malignant gliomas overexpress IL13R conferring the selective cytotoxicity to the agent. Convection-enhanced delivery (CED), a novel direct drug delivery method to tumor and peritumoral region uses positive pressure infusion to generate a pressure gradient that optimizes distribution of macromolecules within the brain. Three phase I studies have been initiated to investigate IL13-PE38QQR as an anti-tumor agent for the treatment of patients with recurrent malignant gliomas. As of January 2003 a total of 46 patients have been treated. The presentation at the March 2003 EANS Local Therapy of Glioma meeting reflects adverse event findings through January 2003 and survival data through March 2003. Intratumoral infusion with or without resection is fairly well-tolerated with corticosteroids prophylaxis particularly for patients with raised intracranial pressure. Post-resection infusion into the peritumoral brain parenchyma also appears to be very well tolerated. Histopathological tumor effect was seen at drug concentrations of 0.5-2.0 microg/mL. Although phase I studies do not focus on efficacy evaluation, prolonged survival times have been observed in this select population of patients. The preclinical data and details and preliminary results of the three clinical trials are reviewed.
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PMID:Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. 1453 68

The cytotoxicity of combinations of a diphtheria toxin-human epidermal growth factor fusion protein (DAB(389)EGF) and a Pseudomonas exotoxin-human interleukin 13 fusion protein (IL13PE38QQR) was tested against 14 human glioma cell lines. After cells were cultured for 48 h with various concentrations of the fusion proteins, the percentage reductions in thymidine incorporation were determined. Seven of fourteen cell lines were highly sensitive to DAB(389)EGF alone, and six cell lines were highly sensitive to IL13PE38QQR alone with IC(90)'s < 100 pM. When combined, synergistic cell killing was observed for seven of the cell lines based upon concave isobolograms and combination indices (CI's) of 0.2 to 0.7. Supraadditive cytotoxicity was confirmed by measurements of induction of apoptosis. Receptor expression was assessed by flow cytometry and confocal microscopy. Marked heterogeneity of expression of EGFR and IL13Ralpha2 was seen on all the glioma cell lines. This heterogeneity may contribute to incomplete cell killing with the individual fusion proteins and synergistic cell kill with the combination. These results suggest that both fusion proteins may yield antitumor effects in patients with recurrent gliomas and that combination fusion protein intracranial therapy of malignant gliomas may yield an improved therapeutic index.
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PMID:Diphtheria toxin-epidermal growth factor fusion protein and Pseudomonas exotoxin-interleukin 13 fusion protein exert synergistic toxicity against human glioblastoma multiforme cells. 1462 23

Central nervous system malignant neoplasias, in particular, glioblastoma multiforme (GBM) have defied all current therapeutic modalities. New therapies involving tumor targeting approach are being explored. This approach relies on the identification of unique or over-expressed cell surface receptors or antigens on tumor cells. In that regard, we have identified receptor for an immune regulatory cytokine, interleukin-13 (IL-13), which is over-expressed on human malignant glioma cell lines and primary tumor cell cultures. To target IL-13 receptors (IL-13R) for cancer therapy, we have developed a recombinant fusion protein composed of IL-13 and a mutated form of Pseudomonas exotoxin (IL13-PE38QQR or IL-13 cytotoxin). The IL-13 cytotoxin was found to be highly selective and potent in killing human GBM cells in vitro while normal cells including immune cells, endothelial cells and normal brain cells were generally spared the cytotoxic effect of IL-13 cytotoxin. This is because these cells either expressed none or expressed low levels of IL-13R. Consistent with in vitro cytotoxic activity, IL-13 cytotoxin mediated remarkable anti-tumor activity to human glioma in animal xenograft models. The direct injection of IL-13 cytotoxin into subcutaneous human GBM tumors grown in nude mice produced complete and durable regression of established tumors. Intravenous and intraperitoneal administration of IL-13 cytotoxin also reduced tumor burden significantly with fewer complete responders. All animals tolerated therapy well with minimal toxicity to vital organs. Pre-clinical safety and toxicity studies were performed in mice, rats and monkeys. Systemic administration of IL-13 cytotoxin appeared to be well tolerated at high doses (up to 50 microg/kg). Intrabrain parenchyma administration of IL-13 cytotoxin at doses up to 100 microg/ml was very well tolerated without any evidence of gross or microscopic necrosis, whereas at 500 microg/ml dose, localized necrosis was observed in normal rat brain. Based on these encouraging pre-clinical studies, three Phase I/II clinical trials in adults with malignant glioma have been initiated. The first clinical trial involves convection-enhanced delivery (CED) of IL-13 cytotoxin into recurrent malignant glioma. This route of IL-13 cytotoxin administration appears to be fairly well tolerated with no neurotoxicity. The second clinical trial involves infusion of IL-13 cytotoxin by CED following tumor resection. The initial stage of the second study assessed histologic effect of drug administered prior to resection. In third one, IL-13 cytotoxin is infused by CED followed by tumor resection. All three clinical trials are currently ongoing.
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PMID:Interleukin-13 receptor-directed cytotoxin for malignant glioma therapy: from bench to bedside. 1464 84

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