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)

The structure of IL-13 receptor (IL-13R) is currently under investigation. Recently, two different human IL-13R chains, termed here IL-13R alpha and -alpha' have been cloned. We have examined various cancer and normal cell lines for the presence of mRNA for IL-13R alpha and alpha, as well as IL-4R p140 (termed beta chain) and IL-2R gamma c chains. In renal cell carcinoma, glioblastoma and ovarian carcinoma (IGROV-1) cell lines, both IL-13R alpha and alpha chains were expressed (type I IL-13R). In epidermoid, colon, ovarian adenocarcinoma (PA-1) and normal mouse fibroblast (COS7) cell lines, only IL-13R alpha' was expressed (type II IL-13R). In hematopoietic TF-1 and EBV-immortalized normal B cell lines only IL-13R alpha' but not alpha chain was expressed along with gamma c (type III or type IV IL-13R). IL-13R alpha' chain was faintly detected in human T cells. All cells expressed the IL-4Rp140 beta chain. These data provide a direct support for our model of IL-13R which consists of three different forms composed of different subunits.
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PMID:Structure of IL-13 receptor: analysis of subunit composition in cancer and immune cells. 929 58

Many of the actions and receptor components of interleukin-13 (IL-13), a pleiotrophic cytokine with immunotherapeutic potential, are shared with IL-4. Because human low-grade astrocytoma cells express IL-4 receptors and their growth is arrested by IL-4, we speculated that IL-13 sensitivity and receptor expression might also be present. The purpose of the current study was to investigate IL-13 receptor components and sensitivity in a series of glial cell lines derived from adult human non-neoplastic cerebral cortex, low-grade astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme. Unlike peripheral blood lymphocytes (PBL), glial cells did not express IL-2 receptor gamma chain. IL-13 receptor alpha-1 (IL-13Ralpha1), however, was present in 11/13 glial lines and PBL. Deficient cell lines were all glioblastoma-derived. All anaplastic astrocytoma and glioblastoma but not other glial lines or PBL expressed IL-13 receptor alpha-2 (IL-13Ralpha2). In non-neoplastic glia, low-grade, and anaplastic astrocytoma, IL-13 decreased DNA synthesis, an effect reversible with antibody to IL-4Ralpha. Results indicate that low-grade astrocytoma cells resemble non-neoplastic glia in terms of IL-13 sensitivity and IL-4Ralpha/IL-13Ralpha1 receptor profile but alterations occur with malignant progression. Glioblastoma cells were uniformly insensitive to IL-13 and, unlike other glia, failed to phosphorylate STAT6 after IL-13 challenge. Data suggest that IL-13 and analysis of IL-13 receptors may have clinical application in glial tumors.
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PMID:Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic glia and low-grade astrocytoma differ from malignant glioma. 1094 14

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

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

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

To develop novel therapeutic agents for the treatment of brain tumors, we have been investigating the expression of unique tumor-associated receptors or antigens on the tumor cell surface. About six years ago, we discovered that human solid tumor cell lines, including human malignant glioma, express high- to intermediate-affinity receptors (R) for a Th2 cell-derived cytokine, interleukin-13 (IL-13). Analysis of the subunit composition of IL-13R in primary explants of malignant glioma cells has demonstrated that IL-13R is composed of three different chains (IL-13R alpha 1, IL-13R alpha 2 and IL-4R alpha, also known as IL-13R alpha', alpha and IL-4R beta, respectively) and that IL-13R alpha 2 chain is overexpressed on these cells. Normal brain tissues express IL-13R alpha 1 and IL-4R alpha chains, but show only marginal expression of IL-13R alpha 2 chain. Thus IL-13R alpha 2 chain appears to be overexpressed on glioma cells and may serve as a novel tumor biomarker or a target for receptor-directed therapeutic agents for brain tumors. To target IL-13 receptors, we have produced a recombinant fusion protein composed of IL-13 and a mutated form of Pseudomonas exotoxin (PE). This cytotoxin, termed IL-13PE38QQR or IL-13 cytotoxin, is highly and specifically cytotoxic to a spectrum of human glioma cell lines. In preclinical models of human glioblastoma tumors growing subcutaneously in immunodeficient mice, IL-13 cytotoxin has been found to have remarkable antitumor activity. The data that emerged from these studies reveal that localized or systemic administration of IL-13 cytotoxin can produce nontoxic drug levels and that IL-13 cytotoxin is potently effective against established glioblastoma tumors. On the basis of these and other preclinical studies, we have begun a phase I clinical trial using IL-13PE38QQR for therapy of recurrent malignant glioma.
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PMID:Preclinical studies with IL-13PE38QQR for therapy of malignant glioma. 1287 31

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

Receptors for interleukin-13 (IL-13R) are overexpressed on several types of solid cancers including gliobastoma, renal cell carcinoma, AIDS Kaposi's sarcoma, and head and neck cancer. Recombinant fusion proteins IL-13 cytotoxin (IL13-PE38QQR or IL13-PE38) have been developed to directly target IL-13R-expressing cancer cells. Although it has been found that IL-13 cytotoxin has a direct potent antitumor activity in vivo in nude mice models of human cancers, the involvement of indirect antitumor effecter molecules such as nitric oxide (NO) is unknown. To address this issue, we assessed the effect of NO inhibiter N(omega)-monomethyl-l-arginine on IL-13 cytotoxin-mediated cytotoxicity and NO2/NO3 production in HN12 head and neck cancer cells. In addition, antitumor effects and NO levels in HN12 and KCCT873 head and neck tumors xenografted s.c. in nude mice when treated with IL-13 cytotoxin were evaluated by tumor measurement, Western blot, and immunohistochemistry analyses. Pretreatment of animals with N(omega)-monomethyl-l-arginine significantly decreased the NO levels and IL-13 cytotoxin-mediated antitumor effects. In addition, depletion of macrophages, known to produce NO, also decreased antitumor activity of IL-13 cytotoxin. Based on these studies, we concluded that NO accelerates antitumor effect of IL-13 cytotoxin on head and neck tumor cells. Because IL-13 cytotoxin is currently being tested in the clinic for the treatment of patients with recurrent glioblastoma maltiforme, our current findings suggest maintaining macrophage and NO-producing cellular function for optimal therapeutic effect of this targeted agent.
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PMID:Nitric oxide accelerates interleukin-13 cytotoxin-mediated regression in head and neck cancer animal model. 1529 30

Interleukin (IL)-13 plays a major role in various inflammatory diseases including cancer, asthma, and allergy. It mediates a variety of different effects on various cell types including B cells, monocytes, natural killer cells, endothelial cells, and fibroblasts. IL-13 binds to two primary receptor chains IL-13Ralpha1 and IL-13Ralpha2. The IL-13Ralpha2 but not IL-13Ralpha1 chain binds IL-13 with high affinity and is overexpressed in a variety of human cancer cells derived from glioma, squamous cell carcinoma of head and neck, and AIDS-associated Kaposi's sarcoma. We have also demonstrated that IL-13Ralpha2 expression is greatly increased in lung cells when mice were challenged intranasally with bleomycin or Aspergillus fumigatus. In addition, IL-13Ralpha2 increased in surgical lung biopsies from patients with usual interstitial pneumonia, nonspecific interstitial pneumonia, and respiratory bronchiolitic interstitial pneumonia of unknown origin. Based on various studies, it is concluded that IL-13Ralpha2-expressing cells are involved in various pulmonary pathological conditions. In contrast, normal tissues such as brain, lung, endothelial cells, and head and neck tissues express IL-13Ralpha1 chain, but show only marginal expression of IL-13Ralpha2 chain. Thus, IL-13Ralpha2 chain may serve as a novel biomarker for diseased cells such as cancer or fibrosis and a target for receptor-directed therapeutic agents. To target IL-13R, a recombinant fusion protein composed of IL-13 and a derivative of Pseudomonas exotoxin (PE) has been produced. This cytotoxin termed as IL-13PE38QQR or IL-13PE38, or IL-13PE is highly and specifically cytotoxic to a variety of human tumor cell lines. In preclinical models of human glioblastoma, head and neck and AIDS-associated Kaposi's cancer, IL-13PE has been found to have significant antitumor activity at a tolerated dose. Several phase I clinical trials have been completed in patients with recurrent malignant glioma. Recently a phase III clinical trial (PRECISE) in patients with recurrent malignant glioma has been completed recruiting a total of 294 patients. IL-13PE cytotoxin has also shown a significant therapeutic effect in preclinical bleomycin or A. fumigatus or Schistosoma mansoni-induced pulmonary pathology including granulomatous fibrosis in mouse models. A clinical study in these diseases has yet to be initiated.
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PMID:Role of interleukin-13 in cancer, pulmonary fibrosis, and other T(H)2-type diseases. 1702 27


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