Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The vast majority of brain cancers (gliomas) express a receptor (R) for interleukin 13 (IL13). In order to achieve specific targeting of the IL13R in gliomas, we have mutagenized human (h) IL13. The mutation was made to alter IL13 interaction with the shared functional IL13/4 normal tissue receptor, but not with the glioma-associated receptor. We have thus produced hIL13.E13K (glutamic acid at position 13 changed to lysine) and fused it to derivatives of Pseudomonas exotoxin A. The hIL13.E13K-based cytotoxins are less active on normal cells and thus less toxic, and are better antitumor agents compared with the cytotoxins containing nonmutagenized hIL13.
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PMID:Novel anti-brain tumor cytotoxins specific for cancer cells. 959 93

Human malignant glioma cell lines express high levels of interleukin-13 receptor (IL-13R). However, the subunit structure of this receptor in primary brain tumor cells is not known. Herein, we examined the subunit composition of IL-13R by analyzing the expression of four different putative subunits of IL-13R complex in 25 primary explants of malignant brain tumors. Reverse transcription-PCR (RT-PCR) of RNA from these tumor cells, normal astrocytes, and normal brain tissue showed that transcripts of IL-13R alpha chain were present in greater abundance in malignant glioma cells compared with normal astrocytes or normal brain tissues. The transcripts for two other chains (e.g., IL-13Ralpha' and IL-4Rbeta), on the other hand, yielded similar PCR positivity in brain tumors as well as in normal samples, whereas transcripts for gammac chain were absent in all brain tumor cells and normal tissues. The specificity of RT-PCR products for these genes was confirmed by oligo liquid hybridization analysis using a radiolabeled sequence-specific internal probe. Indirect immunofluorescence studies for different receptor chains confirmed the RT-PCR results and demonstrated a striking difference in the level of expression of IL-13Ralpha protein between normal astrocytes and malignant astrocytoma cells. These studies establish the IL-13Ralpha subunit as a novel tumor-specific protein that may be useful as a tumor marker, a target for cytotoxin/immunotoxin, or alternatively, a tumor-associated antigen for active, specific immunotherapy.
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PMID:Interleukin-13 receptor alpha chain: a novel tumor-associated transmembrane protein in primary explants of human malignant gliomas. 1145 21

The interleukin-13 receptor alpha2 (IL-13R alpha2) chain is a primary IL-13 binding and internalization component of the IL-13R system. Previous studies have shown that human brain tumors, including glioblastoma multiforme (GBM), overexpress IL-13R alpha2 chain, while normal brain cells do not express this protein or express very low levels of it. To target IL-13R on brain tumor cells, the authors have developed an IL-13R-directed cytotoxin termed IL13-PE38QQR to induce specific cancer cell killing. To investigate the role of IL-13R alpha2 chain in GBM, cells were treated with antisense oligonucleotide or siRNA to IL-13R alpha2 chain, and cellular IL-13 binding and sensitivity to IL-13 cytotoxin were assessed. IL-13R alpha2 gene interference in GBM cells showed decreased ligand binding, and consequently IL-13 cytotoxin exhibited less cytotoxicity to these cells. The authors next evaluated the antitumor activity of IL-13 cytotoxin in native IL-13R-expressing tumors and after gene transfer of IL-13R alpha2 by injecting plasmid in U87MG tumors subcutaneously implanted in nude mice. These mice were then treated with IL-13 cytotoxin. Mean tumor size in mice receiving intraperitoneal or intratumoral IL-13 cytotoxin was significantly smaller in control tumors; however, tumor sizes were much smaller in IL-13R alpha2-transfected tumors. Furthermore, convection-enhanced delivery of IL-13R alpha2 cDNA in intracranially established U87MG glioma followed by IL-13 cytotoxin administration by the same route mediated tumor regression and prolonged survival of animals by 164% compared with control. These results indicate that IL-13R alpha2 chain in GBM cells is essential for IL-13 cytotoxin-induced cytotoxicity and that IL-13R alpha2 chain plays a critical biologic role in IL-13 cytotoxin-mediated therapy for GBM.
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PMID:Evidence that IL-13R alpha2 chain in human glioma cells is responsible for the antitumor activity mediated by receptor-directed cytotoxin therapy. 1583 75

Restricted and high-level expression of interleukin-13 receptor alpha2 (IL-13Ralpha2) in a majority of human malignant gliomas makes this protein an attractive vaccine target. We have previously described the identification of the IL-13Ralpha2(345-353) peptide as a human leukocyte antigen-A2 (HLA-A2)-restricted CTL epitope. However, as it remains unclear how efficiently peptide-based vaccines can induce specific CTLs in patients with malignant gliomas, we have examined whether analogue epitopes could elicit heteroclitic antitumor T-cell responses versus wild-type peptides. We have created three IL-13Ralpha2 analogue peptides by substitutions of the COOH-terminal isoleucine (I) for valine (V) and the NH(2)-terminal tryptophan (W) for either alanine (A), glutamic acid (E), or nonsubstituted (W; designated as 1A9V, 1E9V, and 9V, respectively). In comparison with the native IL-13Ralpha2 epitope, the analogue peptides 9V and 1A9V displayed higher levels of binding affinity and stability in HLA-A2 complexes and yielded an improved stimulatory index for patient-derived, specific CTLs against the native epitope expressed by HLA-A2(+) glioma cells. In HLA-A2-transgenic HHD mice, immunization with the peptides 9V and 1A9V induced enhanced levels of CTL reactivity and protective immunity against an intracranial challenge with IL13Ralpha2-expressing syngeneic tumors when compared with vaccines containing the native IL-13Ralpha2 epitope. These findings indicate highly immunogenic IL-13Ralpha2 peptide analogues may be useful for the development of vaccines capable of effectively expanding IL-13Ralpha2-specific, tumor-reactive CTLs in glioma patients.
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PMID:Identification of interleukin-13 receptor alpha2 peptide analogues capable of inducing improved antiglioma CTL responses. 1674 Jul 28

Transduction of malignant glioma with adenovirus serotype 5 (Ad5) vectors is limited by the low levels of coxsackievirus and adenovirus receptor (CAR) on tumor cells. However, malignant brain tumors have been found to overexpress a glioma-associated receptor, interleukin-13 receptor alpha2 chain (IL-13Ralpha2), a marker of both glial transformation and tumor grade. To selectively target Ad5 to IL-13Ralpha2, we constructed a replication-deficient adenoviral vector that possesses an IL-13 ligand presented by a T4 phage fibritin shaft, and designated the new virus LU-13. Western blot and sequence analyses confirmed proper trimerization and ligand presentation by the T4 fibritin shaft. Confocal microscopy analysis of primary glioma suspensions incubated with viral recombinants showed that LU-13 colocalized with IL-13Ralpha2. Luciferase transduction assays conducted in both primary and passaged glioma cell cultures exhibited at least 10-fold enhanced gene transduction. Moreover, the virus preferentially bound to glioma cells, as documented by increased adenoviral E4 DNA copy number. In vitro competition assays performed with anti-human IL-13 monoclonal antibody confirmed significant attenuation of LU-13 transduction. These results were further confirmed in vivo, where LU-13 showed a 300-fold increase in transgene expression. In summary, we describe here the development of a novel and targeted adenoviral vector that binds IL-13Ralpha2. Our findings confirm the ability of LU-13 to bind IL-13Ralpha2 and increase transgene expression, making it an attractive gene therapy vector for the treatment of malignant glioma in a clinical setting.
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PMID:Novel recombinant adenoviral vector that targets the interleukin-13 receptor alpha2 chain permits effective gene transfer to malignant glioma. 1732 84

We are developing a novel approach to specifically target malignant brain tumor cells for photothermal ablation using antibody-tagged, near infrared-absorbing gold-silica nanoshells, referred to as immunonanoshells. Once localized to tumor cells, these nanoshells are extremely efficient at absorbing near-infrared light and can generate sufficient heat to kill cancer cells upon exposure to laser light. In this study, we evaluated the efficacy of immunonanoshells in vitro against both medulloblastoma and high-grade glioma cell lines. We used an antibody against HER2 to target gold-silica nanoshells to medulloblastoma cells, since HER2 is frequently overexpressed in medulloblastoma. We show that treatment with HER2-targeted nanoshells, but not non-targeted nanoshells, followed by exposure to laser light, can induce cell death in the HER2-overexpressing medulloblastoma cell line Daoy.2, as well as the parental Daoy cell line, which expresses HER2 at a moderate level, but not in dermal fibroblasts that do not express HER2. In an analogous set of experiments, we conjugated gold-silica nanoshells to an antibody against interleukin-13 receptor-alpha 2 (IL13Ralpha2), an antigen that is frequently overexpressed in gliomas. We demonstrate that these immunonanoshells are capable of inducing cell death in two high-grade glioma cell lines that express IL13Ralpha2, U373 and U87, but not in A431 epidermoid carcinoma cells that do not express significant levels of IL13Ralpha2. We believe that the use of antibody-tagged gold-silica nanoshells to selectively target cancer cells presents a promising new strategy for the treatment of central nervous system tumors that will minimize the damage and resulting toxicity to the surrounding normal brain.
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PMID:Immunonanoshells for targeted photothermal ablation in medulloblastoma and glioma: an in vitro evaluation using human cell lines. 1780 88

Human malignant glioma cell lines and adult brain tumors overexpress high levels of interleukin-13 receptor alpha2 chain (IL-13Ralpha2). Because the IL-13Ralpha2 chain is an important target for cancer therapy and prognosis for patients with brainstem glioma (BSG) remains dismal, we investigated the expression of this receptor in specimens of diffusely infiltrative pediatric BSG relative to normal brain tissue. Twenty-eight BSG specimens and 15 normal brain specimens were investigated for IL-13Ralpha2 protein expression by immunohistochemical analysis (IHC) using two different antibodies in two different laboratories. Highly sensitive Q-dot-based IHC and in situ hybridization (ISH) assays were also developed to identify IL-13Ralpha2 protein and RNA in these specimens. The results were evaluated independently in two laboratories in a blinded fashion. By Q-dot IHC or a standard IHC assay, 17 of 28 (61%) tumor specimens showed modest to strong staining for IL-13Ralpha2, while 15 normal brain tissue samples showed weak expression for IL-13Ralpha2 protein. Significant interrater agreement between the two laboratories was seen in the assessment of IL-13Ralpha2 intensity. High-level IL-13Ralpha2 RNA expression was detected in tumor samples by Q-dot ISH, but only weak RNA expression was observed in normal brain. Significant agreement between ISH and IHC assays was observed (simple kappa [kappa] estimate=0.358, weighted kappa=0.89, p=0.001). IL-13Ralpha2 protein and mRNA are expressed to significantly higher levels in BSG than in normal brain tissue. Both IHC and ISH represent robust methods to detect expression of the IL-13Ralpha2 receptor in BSG that could represent an important new drug target for treatment of this disease.
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PMID:Identification of interleukin-13 receptor alpha2 chain overexpression in situ in high-grade diffusely infiltrative pediatric brainstem glioma. 1843 Jul 95

The majority of glioblastoma multiforme (GBM) tumors (80%) overexpress interleukin-13 receptor alpha2 (IL-13Ralpha2), but there is no expression of IL-13Ralpha2 in normal brain. Vaccine strains of measles virus have significant antitumor activity against gliomas. We tested the hypothesis that measles virus entry could be retargeted via the IL-13Ralpha2. MV-GFP-H(AA)-IL-13 was generated from the Edmonston-NSe vaccine strain, by displaying human IL-13 at the C-terminus of the H protein, and introducing CD46 and signaling lymphocyte activation molecule (SLAM)-ablating mutations in H. The IL-13 retargeted virus showed significant cytopathic effect (CPE) against IL-13Ralpha2 overexpressing glioma lines, and lack of CPE/viral replication in normal human astrocytes and normal human fibroblasts not expressing IL-13Ralpha2. In vivo treatment of orthotopically implanted GBM12 xenografts demonstrated significant prolongation of survival in mice treated with the retargeted strain (P < 0.0001), and comparable activity between the IL-13R retargeted strain and MV-GFP (P = 0.6377). In contrast to MV-GFP-treated mice, administration of the retargeted strain in the central nervous system of measles replication-permissive Ifnar(ko) CD46 Ge mice resulted in lack of neurotoxicity. Strains of measles virus retargeted against the glioma-specific IL-13Ralpha2 receptor have comparable therapeutic efficacy, and improved specificity as compared with the unmodified measles virus strain MV-GFP in vitro and in vivo.
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PMID:Interleukin-13 displaying retargeted oncolytic measles virus strains have significant activity against gliomas with improved specificity. 1866 58

Despite advances in surgical technology and radiation therapy, the prognosis in the patients with malignant glioma remains poor. Recent studies show that interleukin-13 receptor [alpha]2 chain (IL-13Ra2), a brain tumor-associated receptor for IL-13, may play a role in immunotherapy for glioblastoma. We thus amplified human IL-13Ra2 gene from the human glioblastoma cell line using RT-PCR and cloned the target gene into the pET-28a, a prokaryotic expressing plasmid. After transformation, the recombinant plasmid expressed a soluble protein induced by IPTG. The purified recombinant protein was shown to be a single band on the SDS-PAGE with a predicated molecular weight of human IL-13Ra2 gene, suggesting that the recombinant protein of human IL-13Ra2 was successfully expressed. Recombinant IL-13Ra2 protein can be used as an anti-tumor vaccine, which may provide a promising new strategy for the treatment of brain malignant gliomas.
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PMID:cDNA clone, prokaryotic expression and purification of human interleukin-13 receptor [alpha]2 chain. 1867 76

Cell-based therapies have intriguing potential for the treatment of a variety of neurological disorders. One such example is genetically engineered cytotoxic T lymphocytes (CTLs) that are being investigated in brain tumor clinical trials. The development of methods for CTL delivery is critical to their use in the laboratory and clinical setting. In our study, we determined whether CTLs can migrate through fibrin matrices and if their migration, survival, and function could be modulated by adding chemokines to the matrix. Our results indicated that CTLs can freely migrate through fibrin matrices. As expected, the addition of the monocyte chemotactic protein-1 (MCP-1), also known as chemokine C-C motif ligand 2 (CCL2), to the surrounding media increased egress of the CTLs out of the fibrin clot. Interleukin (IL) -2 and/or IL-15 embedded in the matrix enhanced T cell survival and further promoted T cell migration. The interleukin-13 receptor alpha 2 specific (IL-13R alpha2) T cells that traveled out of the fibrin clot retained the capacity to kill U251 glioma cells. In summary, CTLs can survive and migrate robustly in fibrin matrices. These processes can be influenced by modification of matrix constituents. We conclude that fibrin matrices may be suitable T cell carriers and can be used to facilitate understanding of T cell interaction with the surrounding microenvironment.
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PMID:Cytotoxic T lymphocyte trafficking and survival in an augmented fibrin matrix carrier. 2249 35


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