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

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

The interleukin (IL) 13 receptor alpha2 (IL13Ralpha2) is a glioma-restricted cell-surface epitope not otherwise detected within the central nervous system. Here, we describe a novel approach for targeting glioblastoma multiforme (GBM) with IL13Ralpha2-specific cytolytic T cells (CTLs) by their genetic modification to express a membrane-tethered IL13 cytokine chimeric T-cell antigen receptor, or zetakine. Our prototype zetakine incorporates an IL13 E13Y mutein for selective binding to IL13Ralpha2. Human IL13-zetakine(+)CD8(+) CTL transfectants display IL13Ralpha2-specific antitumor effector function including tumor cell cytolysis, T(C)1 cytokine production, and zetakine-regulated autocrine proliferation. The E13Y amino acid substitution of the IL13 mutein of the zetakine endows CTL transfectants with the capacity to discriminate between IL13Ralpha2(+) GBM targets from targets expressing IL13Ralpha1. In vivo, the adoptive transfer of IL13-zetakine(+)CD8(+) CTL clones results in the regression of established human glioblastoma orthotopic xenografts. Pilot clinical trials have been initiated to evaluate the feasibility and safety of local-regional delivery of autologous IL13-zetakine redirected CTL clones in patients with recurrent GBM. Our IL13-zetakine is a prototype of a new class of chimeric immunoreceptors that signal through an engineered immune synapse composed of membrane-tethered cytokine muteins bound to cell-surface cytokine receptors on tumors.
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PMID:Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. 1560 87

IL-13 cytotoxin comprised of IL-13 and a mutated form of Pseudomonas exotoxin (fusion protein termed IL-13-PE38QQR) has been shown to inhibit protein synthesis leading to necrotic and apoptotic cell death in glioblastoma cells that express high levels of interleukin-13 receptors (IL-13R). To identify target genes of cell death and other cellular genes with IL-13 receptors in glioblastoma cells, we utilized the cDNA microarrays to analyze global gene expression profiles after IL-13 cytotoxin and IL-13 treatment. IL-13 cytotoxin mediated cytotoxicity to U251 cells in a dose-dependent manner. Hierarchical cluster analysis of differentially expressed genes in U251 glioma cells at different time points after IL-13 cytotoxin treatment showed three major groups, each representing a specific expression pattern. Randomly selected differentially expressed genes from each group were confirmed by RT-PCR analysis. Most down-regulated genes belong to cell adhesion, motility, angiogenesis, DNA repair, and metabolic pathways. While up-regulated genes belong to cell cycle arrest, apoptosis, signaling and various metabolic pathways. Unexpectedly, at early time points, both IL-13 and IL-13 cytotoxin induced several genes belonging to different pathways most notably IL-8, DIO2, END1, and ALDH1A3 indicating that these genes are early response genes and their products may be associated with IL-13R. In addition, IL-13 cytotoxin induced IL-13Ralpha2 mRNA expression during the treatment in glioma cells. Our results indicate that novel cellular genes are involved with IL-13 receptors and that IL-13 cytotoxin induced cell death involves various target genes in human glioblastoma cells. On going studies will determine the role of associated genes and their products in the IL-13R functions in glioma cells.
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PMID:Analysis of target genes induced by IL-13 cytotoxin in human glioblastoma cells. 1580 73

Cancer cells are known to express cell surface molecules such as specific antigens or cytokine receptors, e.g., EGFR, Fas/CD95, gp100, HER-2/neu, IL-13Ralpha2, and MAGE. Among them, interleukin-13 receptor (IL-13R) alpha2 chain is expressed on certain types of cancer cells including glioblastoma, AIDS Kaposi's sarcoma, and head and neck cancer. This protein is one of the receptor components for IL-13, a Th2 cell-derived pleiotropic immune regulatory cytokine. IL-13Ralpha2 chain on these cancer cells can be targeted with a receptor-directed cytotoxin termed IL13-PE to induce specific cancer cell killing, however, this molecule does not mediate cytotoxicity to cells that do not express or express low levels of IL-13Ralpha2. In order to achieve a broad therapeutic window for IL13-PE, plasmid-mediated gene transfer of IL-13Ralpha2 in cancer cells was employed in vitro and in vivo. Cancer cells transfected with IL-13Ralpha2 demonstrated increased binding to IL-13 and sensitivity to IL13-PE in vitro. In vivo intratumoral gene transfer of IL-13Ralpha2 profoundly enhanced the antitumor activity of IL13-PE, providing complete elimination of established tumor in some xenografts. In this review article, current findings from IL-13Ralpha2 gene transfer in a variety of human cancer models in nude mice are summarized. In addition, safety issues and possible future directions utilizing this therapeutic approach are discussed.
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PMID:Cancer gene therapy utilizing interleukin-13 receptor alpha2 chain. 1585 29

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

Previous studies found that allergies are inversely related to risk of glioma. In an earlier publication, using data from a Swedish case-control study, Schwartzbaum et al. report an inverse relation between risk of glioblastoma and four single nucleotide polymorphisms (SNP) on two genes [interleukin (IL)-4Ralpha, IL-13] that are associated with allergies. In addition, recent studies suggest that IL-4 and IL-13 induce cyclooxygenase-2 (COX-2) to resolve brain inflammation. To see whether previous Swedish results (110 cases, 430 controls) would be replicated, we estimated the association between glioblastoma and two IL-4Ralpha (rs1805015, rs1801275) and two IL-13 (rs20541, rs1800925) SNPs and their haplotypes and one COX-2 SNP (-765GC) using additional English, Danish, and Finnish data (217 cases, 1,171 controls). Among general population controls, we evaluated associations between these haplotypes, the COX-2 SNP, and self-reported allergies. Our data did not support our original observations relating individual IL-4Ralpha, IL-13, or COX-2 SNPs to glioblastoma risk. However, the T-G IL-4Ralpha haplotype was associated with glioblastoma risk (odds ratio, 2.26; 95% confidence interval, 1.13-4.52) and there was a suggestion of an inverse relation between this haplotype and hayfever prevalence among controls (odds ratio, 0.38; 95% confidence interval, 0.14-1.03). The lack of support for a link between four IL-4Ralpha and IL-13 SNPs and glioblastoma may reflect the absence of associations or may result from uncontrolled confounding by haplotypes related both to those that we examined and glioblastoma. Nonetheless, the association between the T-G IL-4Ralpha haplotype and glioblastoma risk may indicate a role of immune factors in glioblastoma development.
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PMID:An international case-control study of interleukin-4Ralpha, interleukin-13, and cyclooxygenase-2 polymorphisms and glioblastoma risk. 1800 35

To improve activity of a recombinant IL-13 cytotoxin (CT) comprised of IL-13 spliced to truncated diphtheria toxin (DT(390)), epidermal growth factor (EGF) was added to the same single chain protein. This new recombinant bispecific CT, called DTEGF13, enhanced the killing potency against the human glioblastoma lines, U87MG (0.015 nM) and U118MG (0.02 nM). A similar enhancement was observed against the lung carcinoma cell line, Calu-3 (0.0018 nM). Enhanced activity could not be explained by an increased number of cytokines available for binding since a combination of monospecific DTEGF and DTIL13 did not cause the same enhanced activity. Enhanced activity was dependent on the presence of both cytokines on the same single chain molecule and killing was receptor specific since target receptor negative leukemia cells were unaffected by the highly selective DTEGF13 and cytotoxicity could be blocked with anti-EGFR and anti-IL-13 antibodies. In a xenograft flank tumor model, intratumoral injection of DTEGF13, but not monospecific DTEGF or DTIL13, significantly inhibited the growth of established U87 tumors in nude mice (P < 0.04). In this model, the human EGF and IL-13 components of DTEGF13 are reactive with mouse EGFR and IL-13R, respectively. These studies show that a new co-targeting agent that simultaneously recognizes EGFR and IL-13R is more effective than its monospecific counterparts and that DTEGF13 has therapeutic advantages for glioblastoma.
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PMID:Anti-glioblastoma effect of a recombinant bispecific cytotoxin cotargeting human IL-13 and EGF receptors in a mouse xenograft model. 1808 21

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

Cytokines play important roles in the growth and growth arrest of cancer cells. IL-13 via an IL-4R alpha/IL-13R alpha 1 heterocomplex receptor inhibits the growth of renal cell carcinoma cells (RCC). However, it does not inhibit the growth of glioblastoma cells that express the IL-13R alpha 2 chain. In the present studies we investigated whether melanoma cells express IL-13R alpha 1 and IL-13R alpha 2 chains as well as whether they respond to IL-13. Membrane IL13R alpha 2 was co-expressed with IL-4R alpha and IL-13R alpha 1 chains in three of six tested melanoma cell lines. Furthermore, the IL-13R alpha 2 positive cell lines, release a soluble form of IL-13R alpha 2, specifically under IL-13 but not IL-4 stimulation. The release of soluble IL-13R alpha 2 was inhibited by various metalloproteinase inhibitors and EDTA inhibits the biological response to IL-13.
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PMID:Human melanoma cells release soluble and functional receptors. 1868 68

Human glioblastoma tumors selectively express receptors for interleukin 13 (IL-13). In a previous study, we showed that liposomes, when conjugated with IL-13, will deliver chemotherapeutics to a subcutaneous glioma tumor model in mice much more effectively than conventional unconjugated liposomes. Based on this observation, we developed an intracranial brain tumor model in nude mice using human U87 glioma cells. Mice receiving weekly i.p. injections of 15 mg/kg of doxorubicin encapsulated in IL-13-conjugated liposomes had a 5-fold reduction in the intracranial tumor volume over 6 weeks and four of seven animals survived >200 days after tumor implantation. In contrast, the animals receiving unconjugated liposomes with the same doxorubicin concentration did not survive beyond 35 days and there was no evidence of tumor size reduction. The presence of liposomes with doxorubicin in the tumor was shown by taking advantage of the selective expression of IL-13 receptors on the tumor cells and the endogenous fluorescence of doxorubicin. There was no increase in the indices of toxicity in animals receiving the doxorubicin-containing liposomes. Finally, a model of the blood-brain barrier was used to show that the nanovesicles do not harm the endothelial cells yet maintain their toxicity to astrocytoma cells. This approach is necessary to show the efficacy of this targeting platform for tumors in which the blood-brain barrier is not compromised and as a potential use of the nanovesicle system as a surveillance mechanism to prevent recurrence. These data show that IL-13 targeted nanovesicles are a viable option for the treatment of brain tumors.
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PMID:Efficacy of interleukin-13 receptor-targeted liposomal doxorubicin in the intracranial brain tumor model. 1927 62


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