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)

131I-labeled F(ab')2 fragments of murine monoclonal antibody (MAb) 425 specific to the epidermal growth factor receptor expressed on human gliomas were used in experimental human malignant glioma immunotherapy. Two injections of 150 microCi 131I-labeled 425 F(ab')2 achieved growth inhibition of U-87MG human malignant glioma xenografts in nude mice. This radiolabeled specific MAb F(ab')2 was significantly superior to radiolabeled fragments of an anti-hepatitis virus control MAb A5C3 in influencing tumor growth. However, similar treatment of established human malignant glioma xenografts did not inhibit progressive tumor growth significantly. No clear tumor inhibition was produced by unlabeled MAb 425 F(ab')2. These studies suggest that 131I-labeled MAbs have a significant antitumor effect where unmodified antibody is ineffective. Multiple doses of antibody may achieve an increase in labeled MAb concentration in tumors.
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PMID:Experimental radioimmunotherapy of a xenografted human glioma using 131I-labeled monoclonal antibody to epidermal growth factor receptor. 750 99

The in vitro and in vivo stability and anti-tumour efficacy of the anti-EGFR/anti-CD3 bispecific monoclonal antibody (biMAb), M26.1, were analysed. The interaction of the intact biMAb with Fc receptor I (Fc gamma RI) present on human leucocytes was not observed when the antibody was used as an F(ab')2 fragment. A CD8+ T-cell clone coated with M26.1 F(ab')2 was as effective as the intact biMAb in inducing IGROV1 target cell lysis when tested in a 51Cr-release assay. Variable levels of reduction of F(ab')2 to monovalent F(ab') were observed upon incubation with human ovarian cancer ascitic fluid (OCAF) or with human glioblastoma cavity fluid (GCF), but not with mouse or human sera. Activated lymphocytes coated with F(ab')2 and incubated in vitro with GCF or OCAF for 24 and 48 h respectively maintained their targeting. Thus, the F(ab')2, when present as a soluble molecule, but not when bound to T cells, might lose some functional activity as a consequence of partial reduction to F(ab'). In normal mice, M26.1 F(ab')2 retained full cytotoxic activity in the circulation, and clearance values were similar to those obtained with parental and other MAb F(ab')2. Treatment of IGROV1 tumour-bearing mice with activated human lymphocytes coated with the M26.1 F(ab')2 significantly prolonged survival of the animals compared with tumour-bearing untreated and control mice treated with lymphocytes or F(ab')2 alone. Together, these results suggest the clinical usefulness of bispecific M26.1 F(ab')2 as a targeting agent for local treatment of tumours such as glioma and ovarian cancers that express variable levels of epidermal growth factor receptor (EGFR).
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PMID:In vitro and in vivo stability and anti-tumour efficacy of an anti-EGFR/anti-CD3 F(ab')2 bispecific monoclonal antibody. 754 42

The epidermal growth factor receptor has received much interest as a target for various antineoplastic agents, but a complication is that many normal tissues also express this receptor. We have previously identified in human glial tumors an 801-bp in-frame deletion within the epidermal growth factor receptor gene that created a novel epitope at the junction. By using Western blot assays with a mutant-specific antibody as a rapid and sensitive means for detecting this alteration in primary human tumors, it was found that 57% (26 of 46) of high-grade and 86% (6 of 7) of low-grade glial tumors, but not normal brain, express this protein. This altered receptor was also present in 66% (4 of 6) of pediatric gliomas and 86% (6 of 7) of medulloblastomas, 78% (21 of 27) of breast carcinomas, and 73% (24 of 32) of ovarian carcinomas. The fact that this receptor is frequently found in tumors but not in normal tissue makes it an attractive candidate for various antitumor strategies.
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PMID:Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. 758 29

External beam irradiation has been shown to enhance accumulation of monoclonal antibodies (MAb) in tumors in vivo. This effect is mainly attributed to an unspecific damage of vascular endothelial cells resulting in an increased vascular leakage. The aim of our studies was to determine the effects of external beam radiation on the expression and function of the epidermal growth factor receptor (EGF-R) in vivo. Expression and internalization of EGF-R was tested in vivo, employing 125I-MAb 425 that binds specifically to the human EGF-R. Irradiation of human high-grade glioma cell lines U87-MG and A1207 with increasing doses (0-3600 Rad) of 240 kVp X-rays, markedly enhanced the binding of 125I-MAb 425 to the cell surface. This effect could only be observed for a few days following irradiation. No correlation of the radiation dose and overexpression of EGF-R were found. At the same time, irradiation stimulated significant and dose-dependent internalization of 125I-MAb. Internalization and intranuclear accumulation of 125I-MAb are necessary to explain the radiocytotoxic effects of 125I. The combination of external beam irradiation and labeled MAb 425 showed at least additive effects on tumor cell survival, when the interval between irradiation and MAb treatment was short. Our data support the clinical observations in the adjuvant treatment of high grade gliomas with 125I-MAb 425 following surgery and external beam radiation.
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PMID:Enhancement of monoclonal antibody efficacy: the effect of external beam radiation. 759 Jul 68

A truncated epidermal growth factor receptor (EGFR) expressed from a rearranged and amplified EGFR gene is present at high frequency in gliomas. In this work we show that when this receptor is expressed in NIH3T3 fibroblasts it is partially activated and confers tumorigenicity to this cell line in vivo but no growth advantage in in vitro anchorage-independent growth assays. Because the mutation occurs in the extracellular domain of the receptor, it can be considered to represent a glioma-specific tumour marker. Here we demonstrate that 2 monoclonal antibodies, DH1.1 and DH8.3, raised to a synthetic peptide spanning the unique junctional sequence, can recognise the mutant receptor but not the normal receptor in both denatured and native states. Furthermore, radiolabelled antibody DH8.3 successfully targets tumours expressing this antigen in nude mice.
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PMID:Specific targeting of a mutant, activated FGF receptor found in glioblastoma using a monoclonal antibody. 759 Dec 64

Hypervascularity, focal necrosis, persistent cerebral edema, and rapid cellular proliferation are key histopathologic features of glioblastoma multiforme (GBM), the most common and malignant of human brain tumors. By immunoperoxidase and immunofluorescence, we definitively have demonstrated the presence of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFr) in five out of five human glioma cell lines (U-251MG, U-105MG, D-65MG, D-54MG, and CH-235MG) and in eight human GBM tumor surgical specimens. In vitro experiments with glioma cell lines revealed a consistent and reliable relation between EGFr activation and VEGF production; namely, EGF (1-20 ng/ml) stimulation of glioma cells resulted in a 25-125% increase in secretion of bioactive VEGF. Conditioned media (CM) prepared from EGF-stimulated glioma cell lines produced significant increases in cytosolic free intracellular concentrations of Ca2+ ([Ca2+]i) in human umbilical vein endothelial cells (HUVECs). Neither EGF alone or CM from glioma cultures prepared in the absence of EGF induced [Ca2+]i increases in HUVECs. Preincubation of glioma CM with A4.6.1, a monoclonal antibody to VEGF, completely abolished VEGF-mediated [Ca2+]i transients in HUVECs. Likewise, induction by glioma-derived CM of von Willebrand factor release from HUVECs was completely blocked by A4.6.1 pretreatment. These observations provide a key link in understanding the basic cellular pathophysiology of GBM tumor angiogenesis, increased vascular permeability, and cellular proliferation. Specifically, EGF activation of EGFr expressed on glioma cells leads to enhanced secretion of VEGF by glioma cells. VEGF released by glioma cells in situ most likely accounts for pathognomonic histopathologic and clinical features of GBM tumors in patients, including striking tumor angiogenesis, increased cerebral edema and hypercoagulability manifesting as focal tumor necrosis, deep vein thrombosis, or pulmonary embolism.
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PMID:Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. 768 Feb 47

The epidermal growth factor receptor (EGFR) gene is amplified in over 40% of primary human glioblastomas and overexpressed in the majority. The authors' investigations demonstrate that the function of the EGFR in glioblastomas is distinct from that in other human cancers because it does not appear to mediate the primary growth-promoting effect of EGF. Findings show that the level of EGFR expression does not directly predict the growth response to EGF, with growth stimulated in some cells but inhibited in others when cells were cultured in plastic dishes. On the other hand, when human glioblastoma cells were placed in soft agar cultures, the cell line expressing the highest levels of the EGFR demonstrated considerable colony formation in response to EGF treatment. In addition, cell lines with the highest EGFR levels were also more resistant to the growth-suppressive effects of retinoic acid when maintained in soft agar. These observations suggest that even though the overexpression of the EGFR did not confer a distinct growth advantage to glioma cells cultured on flat culture dishes, the ability of these cells to maintain anchorage-independent growth in soft agar especially in response to EGF and retinoic acid is facilitated. Because anchorage-independent growth is the best in vitro correlate to tumorigenicity, amplification and overexpression of the EGFR in human glioblastoma cells may be in part responsible for the tumorigenic potential of these cells.
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PMID:The role of the epidermal growth factor receptor in human gliomas: I. The control of cell growth. 771 11

Our earlier investigations of the biology of the epidermal growth factor receptor (EGFR) in human gliomas demonstrated that the level of EGFR expression did not directly predict the glioma growth response to EGF, suggesting that the function of the EGFR in glioblastomas might not be limited to mediating the growth effects of EGF. We conducted the current studies to investigate the function(s) of the EGFR not related to growth control in human gliomas. These investigations show that the EGFR mediates the stimulative effects of EGF on glial process extension and glial fibrillary acidic protein (GFAP) expression. In addition, the level of EGFR expression correlates inversely with glioma cell responsiveness to differentiation promoting agents (for example, nerve growth factor and transforming growth factor-beta) that act through transmembrane tyrosine kinase receptors. Thus, glioma lines with a high level of EGFR expression (for example, T-98G cells) responded to fewer differentiation promoting factors than lines with a low level of EGFR expression (such as U-373MG cells). Our results suggest that the EGFR in gliomas may participate in mediating the process extension and GFAP stimulative effects of both EGF and other differentiation promoting agents. These properties represent components of the differentiated state in glia because their expression is stimulated by dibutyryl cyclic adenosine monophosphate in normal astrocytes. The involvement of the EGFR in the expression of these glial specific properties suggests that the EGFR may play an important role in glial differentiation.
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PMID:The role of the epidermal growth factor receptor in human gliomas: II. The control of glial process extension and the expression of glial fibrillary acidic protein. 771 12

The murine MAb 425 (IgG2a) directed against human epidermal growth factor receptor is considered to have therapeutic potential in glioma patients. In order to circumvent immune response in clinical use, the MAb 425 was humanized by CDR-grafting (IgG1). We have studied the distribution of reshaped MAb 425 (EMD 62,000) in Wistar rats and the specific localization in female nude mice bearing human mamma carcinoma xenografts. The 125I-labelled MAb 425 was administered intravenously in a single dose (1 mg/kg) using unspecific human IgG1 antibody as control. The biodistribution was investigated both quantitatively and by whole-body autoradiography. The autoradiographs showed a selective uptake of radioactivity by the tumour tissue. 15 days after administration, radioactivity was bound exclusively to the tumour. Similar results were obtained with the murine monoclonal antibody. Quantitative studies exhibited a tumour-blood ratio of about 5. The study demonstrates that the humanized MAb 425 is selectively localized in human mamma carcinoma xenografted to athymic mice.
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PMID:Distribution of humanized MAb 425 (EMD 62,000) in rats and specific localization in tumor-bearing nude mice. 777 32

Mixed purine-pyrimidine oligodeoxynucleotides were designed to form collinear DNA triplexes with pyrimidine-rich elements in the EGFR gene promoter. Their effects as mediators of human epidermal growth factor receptor (EGFR) gene transcription and subsequent gene expression were evaluated using human squamous cell carcinoma (A431) and human glioma cell line (U251MG and U87MG). Gel shift analysis indicated that the oligonucleotide forms a collinear triplex within the duplex Sp-1 binding site. An in vitro assay system revealed a correlation between triplex formation and the repression of EGFR transcription. We postulate that guanine residues are not always optimum in apposition to G-C pairs to form triple helices in the target. Site-specific oligodeoxynucleotides binding to a DNA duplex may serve as the basis for an alternative program of gene control in vitro.
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PMID:Triplex-forming oligonucleotide binding represses transcription of the human c-erbB gene in glioma. 777 5


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