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 monoclonal antibody (mAb) 806 was raised against the delta2-7 epidermal growth factor receptor (de2-7 EGFR or EGFRvIII), a truncated version of the EGFR commonly expressed in glioma. Unexpectedly, mAb 806 also bound the EGFR expressed by cells exhibiting amplification of the EGFR gene but not to cells or normal tissue expressing the wild-type receptor in the absence of gene amplification. The unique specificity of mAb 806 offers an advantage over current EGFR antibodies, which all display significant binding to the liver and skin in humans. Therefore, we examined the antitumor activity of mAb 806 against human tumor xenografts grown in nude mice. The growth of U87 MG xenografts, a glioma cell line that endogenously expresses approximately 10(5) EGFRs in the absence of gene amplification, was not inhibited by mAb 806. In contrast, mAb 806 significantly inhibited the growth of U87 MG xenografts transfected with the de2-7 EGFR in a dose-dependent manner using both preventative and established tumor models. Significantly, U87 MG cells transfected with the wild-type EGFR, which increased expression to approximately 10(6) EGFRs/cell and mimics the situation of gene amplification, were also inhibited by mAb 806 when grown as xenografts in nude mice. Xenografts treated with mAb 806 all displayed large areas of necrosis that were absent in control tumors. This reduced xenograft viability was not mediated by receptor down-regulation or clonal selection because levels of antigen expression were similar in control and treated groups. The antitumor effect of mAb 806 was not restricted to U87 MG cells because the antibody inhibited the growth of new and established A431 xenografts, a cell line expressing >10(6) EGFRs/cell. This study demonstrates that mAb 806 possesses significant antitumor activity.
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PMID:Monoclonal antibody 806 inhibits the growth of tumor xenografts expressing either the de2-7 or amplified epidermal growth factor receptor (EGFR) but not wild-type EGFR. 1145 74

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and GBMs frequently contain amplifications or mutations of the EGFR gene. The most common mutation results in a truncated receptor tyrosine kinase known as Delta EGFR that signals constitutively and promotes GBM growth. Here, we report that the 45-kDa variant of the protein tyrosine phosphatase TCPTP (TC45) can recognize Delta EGFR as a cellular substrate. TC45 dephosphorylated Delta EGFR in U87MG glioblastoma cells and inhibited mitogen-activated protein kinase ERK2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping TC45-D182A mutant, which is capable of forming stable complexes with TC45 substrates, suppressed the activation of ERK2 but not phosphatidylinositol 3-kinase. TC45 inhibited the proliferation and anchorage-independent growth of Delta EGFR cells but TC45-D182A only inhibited cellular proliferation. Notably, neither TC45 nor TC45-D182A inhibited the proliferation of U87MG cells that did not express Delta EGFR. Delta EGFR activity was necessary for the activation of ERK2, and pharmacological inhibition of ERK2 inhibited the proliferation of Delta EGFR-expressing U87MG cells. Expression of either TC45 or TC45-D182A also suppressed the growth of Delta EGFR-expressing U87MG cells in vivo and prolonged the survival of mice implanted intracerebrally with these tumor cells. These results indicate that TC45 can inhibit the Delta EGFR-mediated activation of ERK2 and suppress the tumorigenicity of Delta EGFR-expressing glioblastoma cells in vivo.
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PMID:The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor. 1151 72

Gene amplification is known to occur frequently in human glioma. Recently we reported cloning of a novel gene termed glioma-amplified sequence 16 (GAS16) by microdissection-mediated cDNA capture. In this article, we demonstrate that GAS16 results from an alternative splicing process of the Ku70 binding protein 3 (KUB3) that is essential for DNA double-strand break repair. The alternative splice product was found in glioblastoma and in normal fetal brain. We determined the amplification frequency of KUB3 in glioma with different grading. We analyzed a total of 102 glioma primary tumors and found KUB3 to be amplified in 12/82 (14%) glioblastomas, 4/13 anaplastic astrocytomas (30%), and 2/4 astrocytomas, but in none of three pilocytic astrocytomas. Northern blot analysis of glioblastoma shows a strong correlation between KUB3 amplification and overexpression. Amplification of KUB3 appears to be independent of other genetic changes frequently associated with the development of gliomas, including EGFR amplification, LOH of TP53, and LOH of chromosome 10. The KUB3 amplification and overexpression may interfere with the function of KUB3 in the DNA-PK complex involved in the maintenance of genome stability and reduction of mutation frequency.
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PMID:KUB3 amplification and overexpression in human gliomas. 1157 79

The death ligands CD95L and Apo2L/TRAIL are promising investigational agents for the treatment of malignant glioma. EGFR is overexpressed in a significant proportion of malignant gliomas in vivo. Here, we report that CD95L-induced cell death is enhanced by EGFR inhibition using tyrphostine AG1478 in 7 of 12 human malignant glioma cell lines. Conversely, CD95-mediated and Apo2L-induced cell death are both inhibited by overexpression of EGFR in LN-229 cells. CD95L-induced cell death augmented by AG1478 is accompanied by enhanced processing of caspase 8. LN-229 cells overexpressing the viral caspase inhibitor, crm-A, are not sensitized to CD95L-induced cell death by AG1478, indicating that EGFR exerts its antiapoptotic properties through a caspase 8-dependent pathway. These data define a modulatory effect of EGFR-activity on death ligand-induced apoptosis and indicate that EGFR inhibition is likely to improve the efficacy of death ligand-based cancer therapies. Furthermore, it is tempting to speculate that EGFR amplification protects tumor cells from death ligand-mediated host immune responses in vivo and that EGFR's effects on death receptor-mediated apoptosis may explain the anti-tumor effects of non-cytotoxic, unarmed anti-EGFR family antibodies.
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PMID:CD95-mediated apoptosis of human glioma cells: modulation by epidermal growth factor receptor activity. 1177 Aug 95

The simultaneous presence of the EGFR and its ligand TGF-alpha in human tumor tissues suggests that autocrine TGF-alpha stimulation drives tumor growth. Here we show that autocrine TGF-alpha stimulation does cause increased tumor growth in vivo, an effect that was proven to be mediated via EGFR activation, and that this TGF-alpha/EGFR autocrine loop was accessible to an EGFR specific tyrosine kinase inhibitor. Clones of the EGFR expressing glioma cell line U-1242 MG were transfected with TGF-alpha cDNA using a tetracycline-inhibitory system for gene expression. TGF-alpha expression was inhibited by the presence of tetracycline, and subcutaneous tumors forming from cell lines injected into nude mice could be inhibited by feeding mice tetracycline. We confirmed that TGF-alpha mRNA and protein were present in these tumors and that, subsequently, the endogenous EGFR was activated. Tumor growth could be inhibited by an EGFR specific tyrosine kinase inhibitor of the type 4-(3-chloroanilino)-6,7-dimethoxy-quinazoline, administered daily by intraperitoneal injection, thereby interrupting the autocrine loop.
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PMID:TGF-alpha-driven tumor growth is inhibited by an EGF receptor tyrosine kinase inhibitor. 1177 76

Monoclonal antibodies (mAbs) such as the tumor-specific anti-epidermal growth factor receptor variant III (EGFRvIII) that are internalized and degraded after cell binding necessitate the use of radioiodination methods that minimize the loss of radioactivity from the tumor cell after intracellular processing. The purpose of the current study was to determine the suitability of N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) for labeling this internalizing mAb. A series of paired-label biodistribution experiments were performed in athymic mice bearing subcutaneous, EGFRvIII-expressing, D-256 human glioma and U87 Delta EGFR xenografts. The tissue distribution of radioiodine activity following injection of anti-EGFRvIII mAb L8A4 labeled using N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) were compared to those for mAb labeled using Iodogen, N-succinimidyl 3-iodo-5-pyridinecarboxylate (SIPC) as well as the Boc-protected precursor of SGMIB. Tumor uptake of radioiodine activity for mAb labeled via SGMIB was significantly higher than co-administered L8A4 radioiodinated by other methods. For example, 3 days after injection, D-256 tumor uptake of L8A4 labeled via SGMIB was 20.4 +/- 4.6% ID/g compared with 11.7 +/- 5.5% ID/g when the SIPC method was used. Thyroid uptake for L8A4 (SGMIB) was up to 36 times lower than L8A4 (Iodogen) and less than 0.35% in all experiments, indicating a low degree of deiodination in vivo. These results suggest that SGMIB may be a useful reagent for the radioiodination of this internalizing anti-EGFRvIII mAb.
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PMID:Improved xenograft targeting of tumor-specific anti-epidermal growth factor receptor variant III antibody labeled using N-succinimidyl 4-guanidinomethyl-3-iodobenzoate. 1178 70

In some respects, the EGFR appears to be an attractive target for tumor-targeted antibody therapy: it is overexpressed in many types of epithelial tumor and inhibition of signaling often induces an anti-tumor effect. The use of EGFR specific antibodies, however, may be limited by uptake in organs that have high endogenous levels of the wild type EGFR such as the liver. The de2-7 EGFR (or EGFRvIII) is a naturally occurring extracellular truncation of the EGFR found in a number of tumor types including glioma, breast, lung and prostate. Antibodies directed to this tumor specific variant of the EGFR provide an alternative targeting strategy, although the lower proportion of tumors that express the de2-7 EGFR restricts this approach. We describe a novel monoclonal antibody (MAb 806) that potentially overcomes the difficulties associated with targeting the EGFR expressed on the surface of tumor cells. MAb 806 bound to de2-7 EGFR transfected U87MG glioma cells (U87MG.Delta 2-7) with high affinity (approximately 1 x 10(9) M(-1)), but did not bind parental cells that express the wild type EGFR. Consistent with this observation, MAb 806 was unable to bind a soluble version of the wild type EGFR containing the extracellular domain. In contrast, immobilization of this extracellular domain to ELISA plates induced saturating and dose response binding of MAb 806, suggesting that MAb 806 can bind the wild type EGFR under certain conditions. MAb 806 also bound to the surface of A431 cells, which due to an amplification of the EGFR gene express large amounts of the EGFR. Interestingly, MAb 806 only recognized 10% of the total EGFR molecules expressed by A431 cells and the binding affinity was lower than that determined for the de2-7 EGFR. MAb 806 specifically targeted U87MG.Delta 2-7 and A431 xenografts grown in nude mice with peak levels in U87MG.Delta 2-7 xenografts detected 8 h after injection. No specific targeting of parental U87MG xenografts was observed. Following binding to U87MG.Delta 2-7 cells, MAb 806 was rapidly internalized by macropinocytosis and subsequently transported to lysosomes, a process that probably contributes to the early targeting peak observed in the xenografts. Thus, MAb 806 can be used to target tumor cells containing amplification of the EGFR gene or de2-7 EGFR but does not bind to the wild type EGFR when expressed on the cell surface.
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PMID:Novel monoclonal antibody specific for the de2-7 epidermal growth factor receptor (EGFR) that also recognizes the EGFR expressed in cells containing amplification of the EGFR gene. 1192 May 91

The recognition of molecular subsets among glioblastomas has raised the question whether distinct mutations in glioblastoma-associated genes may serve as prognostic markers. The present study on glioblastomas (GBM) from 97 consecutively sampled adult patients is based on a clinical, histopathological, immunohistochemical, and molecular genetic analysis. Parameters assessed were age at diagnosis, survival, cell type, proliferation, necrosis, microvascular proliferation, sarcomatous growth, lymphocytic infiltration, thromboses, calcifications, GFAP expression, MIB-1 index, loss of heterozygosity (LOH) of the chromosomal arms 1p, 10p, 10q, 17p, 19q and structural alterations in the TP53, EGFR and PTEN genes. As in previous studies, younger age was significantly associated with better survival. Among the molecular parameters, TP53 mutations and LOH10q emerged as favorable and poor prognostic factors, respectively. TP53 mutations were a favorable prognostic factor independent of whether glioblastomas were primary or secondary. LOH1p or 19q, lesions suspected to be over-represented in long term survivors with malignant glioma, were not associated with better survival. However, the combination of LOH1p and LOH19q defined GBM patients with a significantly better survival. Notably, these patients did not exhibit morphological features reminiscent of oligodendroglioma. These findings indicate that genotyping of glioblastoma may provide clinical information of prognostic importance.
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PMID:Impact of genotype and morphology on the prognosis of glioblastoma. 1193 87

Due to recent biological and technical advances, the list of potentially useful candidate genes is rapidly expanding in the study of brain tumors. However, traditional methods of screening individual genes in individual samples are slow and tedious, often with consumption of precious resources after only a few experiments. This study evaluates the feasibility of high-throughput molecular analysis using fluorescence in situ hybridization (FISH) on glioma tissue microarrays (TMA). A single microarray paraffin block was constructed using 65 WHO grade III and IV astrocytomas, sampled in duplicate with 0.6-mm-diameter punch cores. FISH was used to detect common alterations, such as EGFR amplification, chromosome 7, 9, and 10 aneusomies and deletions of 1p, 19q, PTEN, DMBT1, and p16. Of 585 hybridization sets, 508 (87%) yielded interpretable data, with hybridization failure in 33 (5.5%) and dislodged tissue in 44 sets (7.5%), respectively. Glioblastomas harbored significantly more alterations than anaplastic astrocytomas, with the overall frequencies of alterations similar to those reported using other techniques. The overall concordance rate between paired tumor core samples was 93%. We conclude that TMA-FISH is an efficient and reliable method for detecting molecular alterations in high-grade astrocytomas.
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PMID:High-throughput molecular profiling of high-grade astrocytomas: the utility of fluorescence in situ hybridization on tissue microarrays (TMA-FISH). 1248 70

The EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) gefitinib ("Iressa", ZD1839), a reversible growth inhibitor of EGFR-expressing tumour cells, has been shown to enhance the antitumour effect of ionising radiation, and also to increase the uptake of radioiodinated EGF. Thus, combination of gefitinib treatment and radionuclide targeting is an interesting option for therapy of brain tumours that are difficult to treat with conventional methods. The aim of this study was to evaluate how pre-treatment with gefitinib affects binding of astatinated EGF ((211)At-EGF) to cultured glioma U343 cells, which express high levels of EGFR. The growth of U343 cells in the presence of gefitinib was investigated, and it was found that gefitinib does not significantly inhibit the growth of these cells. Nevertheless, the uptake of (211)At-EGF in U343 cells was markedly increased (up to 3.5 times) in cells pre-treated with gefitinib (1 microM). This indicates that a combination of gefitinib treatment and radionuclide targeting to EGFR might be a useful therapeutic modality, even for patients who do not respond to treatment with gefitinib alone.
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PMID:Treatment of cultured glioma cells with the EGFR-TKI gefitinib ("Iressa", ZD1839) increases the uptake of astatinated EGF despite the absence of gefitinib-mediated growth inhibition. 1274 Jul 21


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