UMLS:C0017636 - FACTA Search

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prognosis of glioblastoma multiforme remains poor despite advances in treatment by surgery, irradiation, and chemotherapy. Many malignant gliomas overexpress growth factor receptors. The possibility of targeting these receptors with selective cytotoxic molecules constructed by fusing deoxyribonucleic acid (DNA)-encoding mutant forms of Pseudomonas exotoxin A (PE) with complementary DNA-encoding growth factors was investigated. Several recombinant toxins have been produced, including those in which transforming growth factor (TGF)-alpha, insulin-like growth factor (IGF)-I, and acidic fibroblast growth factor (FGF) were fused to mutant forms of PE lacking the native cell-binding domain. These recombinant proteins are cytotoxic to cells that express specific cell-surface receptors. The cytotoxic activity of TGF-alpha, IGF-I, and acidic FGF chimeric toxins was tested in vitro against human glioblastoma cell lines. Each recombinant toxin exhibited potent and specific killing of cells. The TGF-alpha-PE40 construct was cytotoxic to seven of the eight cell lines and was active at concentrations as low as 0.5 ng/ml (1.1 x 10(-11) M). The acidic FGF-PE40 toxin was also active on seven of the eight cell lines but was 50-fold less active than the TGF-alpha-PE40. The IGF-I-PE40 construct was active on only two cell lines. To determine the possible therapeutic effect in animals, TGF-alpha-PE40 was administered to nude mice bearing subcutaneous human glioblastoma xenografts. The animals were treated for 7 days via a continuous infusion pump placed in the peritoneal cavity. A constant serum level of TGF-alpha-PE40 was achieved that was nontoxic to the mice yet caused a reduction in tumor volume and retarded growth beyond the treatment period. The overexpression of the epidermal growth factor receptor in glioblastomas multiforme and the potency and specificity of the TGF-alpha-PE40 construct designed to target this receptor suggests that TGF-alpha-PE40 has the potential to be an effective antitumor agent for the adjuvant therapy of these carcinomas.
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PMID:Cytotoxicity and antitumor effects of growth factor-toxin fusion proteins on human glioblastoma multiforme cells. 769 18

Glioblastoma, glioma or neuroblastoma cells were examined for the expression of IL-4 receptors (IL-4R) by flow cytometric analysis and 125I-IL-4 binding. These cancer cell lines expressed IL-4R which were of high affinity (KD = 700 x 10(-12) M) on glioblastoma cells. To investigate the function of these receptors and to target potent cytotoxic antitumor agents to human neurological cancers, we utilized IL4-PE4E, which is composed of IL-4 and mutant Pseudomonas exotoxin (IL4-PE4E). This chimeric molecule was cytotoxic toward human glioblastoma, neuroblastoma and glioma tumor cells in a dose-dependent manner. The cytotoxicity of IL4-PE4E was specific, since it was neutralized by excess IL-4, and by an anti-IL-4 monoclonal antibody in all types of brain tumor tested. IL2-PE4E and IL6-PE4E were not cytotoxic, nor was an IL4-PE4E mutant lacking ADP-ribosylating activity, indicating the IL4-PE4E-mediated cytotoxicity of the brain tumor cells required both IL-4R binding and enzymatic toxin activity. These data indicate that human neurological cancer cells express IL-4R which are targets for the cytotoxic effects of IL4-toxin. In addition, our data also suggest that IL4-PE4E should be studied further as a potential treatment for human neurological cancers.
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PMID:Human neurological cancer cells express interleukin-4 (IL-4) receptors which are targets for the toxic effects of IL4-Pseudomonas exotoxin chimeric protein. 805 54

Epidermal growth factor receptor (EGFR) is amplified or overexpressed in many malignant gliomas and other primary brain tumors but is low or undetectable in normal brain. In the present study, this differential expression has been exploited for targeted brain tumor therapy using a TGF-alpha-Pseudomonas exotoxin recombinant toxin, TGF-alpha-PE38. In vitro experiments demonstrate that the cytotoxicity of this fusion protein is primarily determined by tumor EGFR expression and that TGF-alpha-PE38 cytotoxicity is abolished by pretreatment with excess epidermal growth factor. Treatment with i.p. TGF-alpha-PE38 in nude mice bearing glioblastoma or medulloblastoma s.c. xenografts produced tumor regression and growth delay. For intracranial xenograft implants treated with i.p. TGF-alpha-PE38, significant increases in median survival were noted only for tumors with the highest EGFR expression. However, intracranial tumors treated with a single intratumoral injection of TGF-alpha-PE38 showed increased survival in all xenografts tested. These results indicate that TGF-alpha-PE38 is active against primary human brain tumors ranging from moderate to high EGFR expression. For intracranial tumors, however, the higher survival rates produced by intracranial injection of TGF-alpha-PE38 than by continuous i.p. administration suggest that increased drug clearance or impaired drug delivery reduces the efficacy of systemic TGF-alpha-PE38. Direct delivery of TGF-alpha-PE38 into brain tumors by controlled-release biodegradable polymers or intratumoral implanted catheters, or intrathecal administration into the colony stimulating factor of patients with leptomeningeal metastasis, may represent clinically useful applications of recombinant toxin therapy in tumors with high EGFR expression.
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PMID:Transforming growth factor-alpha-Pseudomonas exotoxin fusion protein (TGF-alpha-PE38) treatment of subcutaneous and intracranial human glioma and medulloblastoma xenografts in athymic mice. 831 55

EGFRvIII is a mutant epidermal growth factor receptor found in glioblastoma, and in carcinoma of the breast, ovary, and lung. The mutant receptor has a deletion in its extracellular domain that results in the formation of a new, tumor-specific extracellular sequence. Mice were immunized with a synthetic peptide corresponding to this sequence and purified EGFRvIII. A single chain antibody variable domain (scFv) phage display library of 8 x 10(6) members was made from the spleen of one immunized mouse. A scFv specific for EGFRvIII was isolated from this library by panning with successively decreasing amounts of synthetic peptide. This was used to make an immunotoxin by fusing the scFv DNA sequence to sequences coding for domains II and III of Pseudomonas exotoxin A. Purified immunotoxin had a Kd of 22 nM for peptide and a Kd of 11 nM for cell-surface EGFRvIII. The immunotoxin was very cytotoxic to cells expressing EGFRvIII, with an IC50 of 1 ng/ml (16 pM) on mouse fibroblasts transfected with EGFRvIII and an IC50 of 7-10 ng/ml (110-160 pM) on transfected glioblastoma cells. There was no cytotoxic activity at 1000 ng/ml on the untransfected parent glioblastoma cell line. The immunotoxin was completely stable upon incubation at 37 degrees C for 24 h in human serum. The combination of good affinity, cytotoxicity and stability make this immunotoxin a candidate for further preclinical evaluation.
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PMID:Recombinant immunotoxins specific for a mutant epidermal growth factor receptor: targeting with a single chain antibody variable domain isolated by phage display. 896 38

Effective treatment is lacking for malignant glioblastoma/astrocytoma. We have identified interleukin-4 receptors (IL-4R) on human malignant astrocytoma. We demonstrate that 16 of 21 surgical samples of high-grade astrocytoma and glioblastoma but not normal brain tissues expressed IL-4R as assessed by reverse transcriptase PCR. We further demonstrate that human malignant astrocytoma cell lines express high-affinity IL-4R. Using a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin A, we observed that this toxin IL4(38-37)-PE38KDEL) is highly cytotoxic to IL-4R-bearing glioblastoma cells. Compared with a previously reported IL4-PE chimeric protein (IL-PE4E), IL4(38-37)-PE38KDEL bound with higher affinity and was 3-30-fold more cytotoxic to glioblastoma cell lines. Upon intrathecal administration in monkeys, high cerebrospinal fluid IL4(38-37)-PE38KDEL levels were achieved using 2- and 6-microg/kg doses without any central nervous system or other abnormalities. IL4(38-37)-PE38KDEL levels were not detectable in the serum of any monkey studied. When IL4(38-37)-PE38KDEL was injected into the right frontal cortex of rats, localized necrosis was observed at 1000-ng/ml doses but not at < or = 100-ng/ml doses. We conclude that by localized administration, nontoxic levels of IL4(38-37)-PE38KDEL can be achieved, which may have significant cytotoxic activity against malignant astrocytoma.
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PMID:Preclinical development of a recombinant toxin containing circularly permuted interleukin 4 and truncated Pseudomonas exotoxin for therapy of malignant astrocytoma. 1145 21

No curative therapy is available for malignant gliomas. We have discovered that human glioblastoma cells express high affinity interleukin-4 receptor (IL-4R), which is an attractive target for receptor-directed IL-4 toxin therapy. The IL-4 toxin, IL-4(38-37)-PE38KDEL, is a fusion protein containing translocation and enzymatic domains of Pseudomonas exotoxin and a circularly permuted human IL-4. The IL-4 toxin binds specifically to the IL-4R and is highly cytotoxic to glioblastoma cells, as determined by clonogenic and protein synthesis inhibition assays. Intratumoral administration of the IL-4 toxin given on alternate days for 3-4 doses into U251 glioblastoma flank tumors in nude mice, showed a complete remission of small (approximately 13 mm3) and large (approximately 60 mm3) tumors in all animals, without any evidence of toxicity. A significant antitumor activity was also observed when the IL-4 toxin was administered via i.p. and i.v. routes. These results demonstrate that the IL-4 toxin may be a new therapeutic drug for the treatment of human glioblastoma. Therefore, we have begun a Phase I clinical trial with IL-4(38-37)-PE38KDEL for treatment of human glioblastoma.
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PMID:Complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy. 972 74

About 12,000 Americans are diagnosed with malignant astrocytoma each year. Despite surgery, radiotherapy, and chemotherapy, the prognosis of these patients remains poor. Targeted toxins based on the identification of novel antigens or receptors provide a promising new approach to treating cancer. We have identified one such cell surface protein in the form of interleukin (IL)-4 receptors (IL-4R) on human malignant astrocytoma. Normal brain tissues from frontal cortex and temporal lobe cortex do not express IL-4R. To target IL-4R, we generated a chimeric fusion protein composed of IL-4 and Pseudomonas exotoxin (IL4-PE). This toxin is highly cytotoxic to IL-4R-bearing human brain cancer cells. Preclinical toxicologic experiments were performed in mice, rats, and guinea pigs to determine an maximum tolerated dose. Intrathecal administration in cynomolgus monkeys produced high cerebrospinal fluid levels without any central nervous system or other abnormalities. When IL4-PE was injected into the right frontal cortex of rats, localized necrosis was observed at 1,000 but not < or =100 microg/ml doses. Intravenous administration of this biologic to monkeys produced reversible grade 3 or grade 4 elevations of hepatic enzymes in a dose-dependent manner. These results indicate that localized administration can produce nontoxic levels of IL4-PE that may have significant activity against astrocytoma. In vivo experiments with nude mice have demonstrated that IL4-PE has significant antitumor activity against human glioblastoma tumor model. Intratumor administration of IL4-PE has been initiated for the treatment of malignant astrocytoma in a phase I clinical trial.
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PMID:Development of a recombinant interleukin-4-Pseudomonas exotoxin for therapy of glioblastoma. 1036 74

Human glioblastoma but not normal brain cells express numerous receptors for the cytokine interleukin (IL)-4. To target these receptors, we have investigated the safety and activity of directly infusing IL-4(38-37)-PE38KDEL, a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin (PE), into recurrent malignant high-grade gliomas. IL-4(38-37)-PE38KDEL (IL-4-toxin) was infused over a 4-8-day period into gliomas of nine patients by one to three stereotactically placed catheters. No apparent systemic toxicity occurred in any patient. The infusion of IL-4-toxin in six of nine patients showed glioma necrosis as evidenced by diminished gadolinium enhancement on magnetic resonance imaging. Seven of nine patients underwent craniotomy because of increased intracranial pressure at 16-101 days after the beginning of infusion. In six of these seven patients, partial-to-extensive tumor necrosis with edema was confirmed pathologically. No histological evidence of neurotoxicity to normal brain was identified in any patient. Two patients were not operated on; by magnetic resonance imaging, one showed mottled gadolinium enhancement, and the other showed extensive necrosis of tumor leading to complete remission; this patient remains disease-free > 18 months after the procedure. We conclude that direct glioma injection of IL-4(38-37)-PE38KDEL is safe without systemic toxicity. Local toxicity seemed attributable mainly to tumor necrosis or occasionally to the volume of infusion. Histological evidence of toxicity to normal brain was not observed and in many patients, could be pathologically excluded. Additional patients are being treated to determine the maximal tolerated concentration and volume of IL-4(38-37)-PE38KDEL.
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PMID:Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma. 1087 64

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

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