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)

Chloroquine has been shown to increase the cellular retention and nuclear incorporation of 125I-labeled monoclonal antibody (MAb) 425, a murine anti-epidermal growth factor receptor monoclonal antibody, in human high-grade glioma cells in vitro. The objective of this study was to examine the effect of chloroquine on the biodistribution of 125I-MAb 425 in an intracerebral xenogeneic transplant of glioma cells. Nude rats were stereotaxically implanted in the right hemisphere with A1207 human high-grade glioma cells. After 14 days, animals were injected i.v. with chloroquine (40 mg/kg) followed 2 h later by an 125I-MAb 425 (9 MBq) infusion. Tissue distributions were performed up to 168 h post 125I-MAb 425 injection. From 24 to 168 h, tumor-to-contralateral left brain ratios increased from 9 to 15 for 125I-MAb 425 alone, and 7 to 13 for the 125I-MAb 425/chloroquine combination, respectively. A single administration of chloroquine did not result in any significant difference in radiolabeled MAb accumulation in either the tumor site or other tissues. We conclude that chloroquine did not increase the amount of 125I-MAb 425 into the tumor; however, it is safe to administer i.v. at the 40 mg/kg dose. Under these experimental conditions, the increased radioactive accumulation observed for in vitro data did not translate into similar in vivo results.
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PMID:Biodistribution of 125I-MAb 425 in a human glioma xenograft model: effect of chloroquine. 908 35

Our aim has been to understand the features of erbB receptor homo- and heterodimer assembly to develop approaches to disrupt receptor activation. We have developed a general approach to cause erbB receptor-specific trans inhibition of human neoplasia. The clonal progression of human astrocytomas to a more malignant phenotype often involves the amplification and overexpression of the epidermal growth factor receptor (EGFr) gene. We have selectively targeted the EGFr in human glioblastoma cells with kinase-deficient mutants of the erbB family derived from the ectodomain of the Neu oncogene that are able to form heterodimers with EGFr and inhibit EGFr-dependent phenotypes. In EGFr-positive U87MG human glioblastoma cells, expression of the Neu ectodomain inhibits EGF-, but not platelet-derived growth factor-, induced DNA synthesis; inhibits cell proliferation in the presence of EGF, but not platelet-derived growth factor; inhibits the ability of U87MG to form colonies in soft agar; and inhibits transforming efficiency in athymic mice. These studies establish that EGFr-mediated signal transduction is important in the maintenance of malignant glioma, and that trans receptor inhibition is a novel way to abrogate abnormal growth of these tumors. Neu ectodomains will be useful in determining the manner in which the EGFr contributes to glial tumorigenesis and in the design of pharmaceuticals that disable erbB family oncoproteins. In addition, these studies provide a rationale for the application of the Neu ectodomain in gene therapy approaches to human malignant glioma and, potentially, to other systemic epithelial malignancies expressing erbB family receptors.
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PMID:Trans receptor inhibition of human glioblastoma cells by erbB family ectodomains. 909 79

DNA amplification is a common mechanism invoked by many human tumors to elicit overexpression of genes whose products are involved in drug resistance or cell proliferation. Although amplified regions in tumor DNA may exceed several megabases in size, segments of amplicons with a high probability of containing gene sequences may be amenable to detection by restriction landmark genomic scanning (RLGS), a high-resolution DNA analysis that separates labeled NotI fragments in two dimensions. Here, we tested this by applying RLGS to matched samples of glioma and normal brain DNA and found tumor-specific amplification of the gene encoding cyclin-dependent kinase 6 (CDK6), an observation not previously reported in human tumors. The CDK6 gene has been localized to chromosome 7q21-22, but in the gliomas studied here, it was not coamplified with either the syntenic MET (7q31) or epidermal growth factor receptor (7p11-p12) genes, suggesting that this may be part of a novel amplicon in gliomas. We then corroborated this finding by identifying both amplification-associated and amplification-independent increases in CDK6 protein levels in gliomas relative to matched normal brain samples. These data implicate the CDK6 gene in genomic amplification and illustrate the potential of RLGS for the more general identification and cloning of novel genes that are amplified in human cancer.
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PMID:Cyclin-dependent kinase 6 (CDK6) amplification in human gliomas identified using two-dimensional separation of genomic DNA. 910 8

High grade gliomas may have amplified expression of the epidermal growth factor receptor (EGFR) gene c-erb-B, which often is associated with increased expression of transmembrane EGFR. The purpose of the present study was to develop a method for labeling EGF with 99mTc and to determine whether the resulting radioligand would localize, following intracerebral injection, in rats bearing EGFR-positive gliomas. EGF has a relatively low molecular mass (approximately 6 kDa) compared to monoclonal antibodies, and this has allowed smaller bioconjugates, which should diffuse more rapidly within the brain and more effectively target disseminated glioma cells, to be constructed. In the present study, EGF has been labeled with either 131I or 99mTc, and in vitro uptake of the resulting radioligand has been investigated using C6EGFR rat glioma cells, which had been transfected with the EGFR gene. Cellular uptake of 131I radioactivity peaked after approximately 30 min of incubation with [131I]EGF, following which time it declined, while 99mTc radioactivity continued to increase over a 6 h incubation with [99mTc]-EGF. To determine if radiolabeled EGF had in vivo tumor-localizing properties, C6EGFR glioma cells were implanted stereotactically into the brains of Fischer rats. Four weeks later, either 99mTc- or 131I-labeled EGF was injected intracerebrally into normal or glioma-bearing animals using the same stereotactic coordinates. External gamma scintigraphy revealed that 131I radioactivity disappeared rapidly from the brain regions of tumor-bearing animals compared to 99mTc, approximately 50% of which remained in the tumor for up to 12 h. In contrast, only approximately 20% remained in the brains of non-tumor-bearing animals after 6 h. These studies are the first to describe a method for radiolabeling EGF with 99mTc and to detect it by external scintigraphy in the brains of tumor-bearing animals.
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PMID:Radiolabeling of epidermal growth factor with 99mTc and in vivo localization following intracerebral injection into normal and glioma-bearing rats. 917 33

Human gliomas occasionally show rearrangements with deletions (exons II to VII) in the epidermal growth factor receptor (EGFR) gene, resulting in the expression of aberrant EGFR mRNA. This abnormality of EGFR gene expression is closely related to the malignancy of glioma. However, this EGFR gene abnormality has not been demonstrated directly in the glioma cells themselves, as gliomas consist of heterogeneous tissue components. In this study, we used in situ hybridization (ISH) to detect aberrant EGFR mRNA in the tumor cells in 26 human gliomas and 19 human glioma xenografts. We used digoxigenin (DIG)-labeled antisense oligonucleotide probes for ISH, which demonstrated aberrant EGFR mRNA in 2 of the 26 gliomas and in 3 of the 19 human glioma xenografts. ISH with an aberrant EGFR-specific probe (oligo-PA) revealed that EGFR mRNA was absent from multinucleated giant cells and from proliferating endothelial cells, but this transcript was present in small glioma cells. Identical aberrant EGFR mRNA was confirmed in these glioma and human glioma xenografts by Southern blotting. Northern blotting, and by reverse transcription-polymerase chain reaction (RT-PCR). These findings suggest that small tumor cells specifically express the aberrant EGFR mRNA in certain high grade gliomas.
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PMID:Localization of aberrant messenger RNA of epidermal growth factor receptor (EGFR) in malignant glioma. 921 93

Despite the use of multimodal therapy, higher-grade glioma is still uniformly fatal in the adult population. There is a considerable difference between the length of survival in each given patient, even within the same tumor type and malignancy grade group, suggesting that there are factors that might differentially influence outcome. To identify such factors, 107 patients with anaplastic or malignant glioma were retrospectively investigated. Clinical parameters and paraclinical data on the p53, mdm2, and EGFR genes at the DNA or protein level were evaluated by univariate analysis and Cox proportional hazards regression modeling. Kaplan-Meier survival estimation demonstrated that immunohistochemical positivity for mdm2 protein in patients with anaplastic astrocytoma or with glioblastoma multiforme was associated with a shorter survival time (p = 0.02). P53 gene mutations and immunopositivity for the epidermal growth factor receptor (EGFR) protein were not significantly related to poor prognosis. The Cox proportional hazards model revealed immunohistochemical positivity for p53, mdm2, or for both of them, the presence of postoperative irradiation, and the extent of surgical resection of tumor to be variables significantly associated with prolonged survival. EGFR overexpression, age over 60 years, and Karnofsky performance score below 40 points did not significantly shorten survival time. In conclusion, the present study identified immunohistochemically detected mdm2-protein overexpression as a statistically significant negative prognostic parameter in patients bearing anaplastic or malignant glioma. Association analysis of variables revealed a possible correlation between mdm2 and p53, which is also consistent with the biological interaction mode of both proteins in vivo.
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PMID:Prognostic factors in malignant glioma: influence of the overexpression of oncogene and tumor-suppressor gene products on survival. 926 37

To identify antigenic differences between gliomas and normal brain, we have immunohistochemically studied the expression of lymphocyte adhesion molecules (ICAM-1, ICAM-2, ICAM-3, VCAM-1, E-selectin and CD58), epidermal growth factor receptor (EGFR) and extracellular matrix proteins (collagen IV, fibronectin, laminin, merosin, tenascin and vitronectin) in these tissues. Gliomas expressed high levels of ICAM-1, CD58 (LFA-3), EGFR, tenascin and vitronectin, whereas only very low levels were detected in normal brain. VCAM-1 expression was detected in 15 out of 25 gliomas but not in normal brain. The presence of VCAM-1 in gliomas was verified by immunoblotting and RNase protection assay, and in glioma cell lines by Northern blotting. Expression of VCAM-1 in gliomas may partially explain lymphocytic infiltration, and anti-VCAM-1 antibodies may be of potential in antibody mixtures for targeted therapy of gliomas.
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PMID:Lymphocyte adhesion molecule ligands and extracellular matrix proteins in gliomas and normal brain: expression of VCAM-1 in gliomas. 929 90

The potential of therapeutic targeting of tumor cell surface epidermal growth factor receptors (EGFRs) by modified ligands or specific antibodies has been limited by the normal tissue distribution of the receptor. The identification and characterization of a variant of this receptor, EGFRvIII, which is not expressed in normal tissues but has been described in gliomas, non-small cell lung carcinomas, and breast carcinomas, has provided a highly specific, internalizing target for antibody-mediated approaches. To determine the feasibility of immunotargeting EGFRvIII, we have assessed the qualitative distribution and quantitative expression at both the population and cellular levels of EGFRvIII in 21 biopsy samples of human gliomas by indirect analytical and quantitative flow cytometry and by immunohistochemical assay of frozen and formalin-fixed tissue. Consistent with previous reports, 50% of gliomas tested (1 of 2 anaplastic astrocytomas, 7 of 12 glioblastoma multiforme, and 2 of 6 oligodendrogliomas) expressed EGFRvIII, as determined by a minimum of 2 separate assays. Minimum estimates of the proportion of positive tumor cells in these populations ranged from 37-86%; in four of five cases in which quantitation of the EGFRvIII density/cell was performed, values of 2.7-6.8 x 10(5) were obtained with monoclonal antibody (mAb) L8A4 (EGFRvIII specific), levels consistent with successful in vivo immunotargeting. Confocal microscopic analysis confirmed that the subcellular localization of EGFRvIII was identical to that described for EGFR: predominant cell membrane expression, with some perinuclear distribution suggestive of localization to the Golgi region. Neither EGFR nor EGFRvIII was found within the nucleus. This study establishes for the first time that approximately 50% of human glioma biopsies contain cell populations expressing a sufficient number of membrane-expressed EGFRvIIIs to mediate specific anti-EGFRvIII mAb localization. Coupled with previous demonstrations of the rapid internalization of specific mAb-EGFRvIII complexes and the susceptibility of the targeted cells to isotope or toxin-mediated cytotoxicity, this study establishes the validity of targeting EGFRvIII for therapy of mutant receptor-positive gliomas, breast carcinomas, and non-small cell lung carcinomas.
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PMID:Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. 930 4

The gene for epidermal growth factor receptor (EGFR) is amplified or overexpressed in high-grade gliomas but is low or undetectable in normal brain. Recently, there has been increasing interest in using epidermal growth factor (EGF)-based bioconjugates as targeting agents for brain tumors. In the present study, we have investigated the potential use of boronated EGF as a delivery agent for boron neutron capture therapy, which is based on the capture reaction that occurs when 10B, a stable isotope, is irradiated with low-energy thermal neutrons. A fourth generation starburst dendrimer was boronated and linked to EGF using heterobifunctional reagents. Either wild-type or EGFR gene transduced C6 glioma cells (C6EGFR), which expressed 10(5)-10(6) receptor sites/cell, were stereotactically implanted into the right cerebral hemisphere of Fischer rats. Four weeks later, the rats received either i.v. or intratumoral (i.t.) injection of 131I-labeled boronated starburst dendrimer (BSD) or BSD-EGF. The biodistribution of 131I-BSD-EGF and 131I-BSD was studied by means of whole-body scintigraphy, autoradiography, and gamma scintillation counting. Following i.t. injection of 131I-BSD-EGF, 21.8% of the injected dose per gram tissue (% ID/g) was localized in C6EGFR tumors at 24 h and 16.3% at 48 h compared to 5 and 1.3% ID/g in C6 wild-type tumors, respectively, and 0.01 and 0.006% ID/g, respectively, for i.v. injected animals at the corresponding times. In contrast, following i.t. injection of BSD-EGF, only 0.01-0.1% ID/g was localized in the liver and spleen at 24 and 48 h compared to 5-12% ID/g following i.v. injection. Our data indicate that direct i.t. injection can selectively deliver BSD-EGF to EGFR-positive gliomas and suggest that intracerebral administration may be the most effective way for delivering EGF-based bioconjugates to EGFR-positive brain tumors.
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PMID:Intratumoral delivery of boronated epidermal growth factor for neutron capture therapy of brain tumors. 933 Oct 95

Loss of heterozygosity (LOH) from chromosome 10 is a hallmark of glioblastoma, the most malignant (grade IV) form of glioma. A candidate tumor suppressor gene, PTEN/MMAC1, that may be targeted for deletion in association with chromosome 10 LOH has recently been identified. Here we have investigated 63 glioblastomas for PTEN/MMAC1 alterations and identified DNA sequence changes that would affect the encoded protein in 17 (27%) tumors. Microsatellite analyses of normal-tumor DNA pairs were performed on 14 of these cases and revealed LOH at locations flanking and/or near PTEN/MMAC1 in all but 1 instance, suggesting that deletion of the remaining wild-type allele had occurred in the large majority of tumors with PTEN/MMAC1 mutations. Competitive PCR assays were developed to address the possible occurrence of PTEN/MMAC1 homozygous deletions in glioblastomas, and this analysis identified three samples having loss of both PTEN/MMAC1 alleles. EGFR amplification was determined to occur at similar frequencies among cases with or without PTEN/MMAC1 homozygous deletions or mutations, suggesting that a growth-promoting effect resulting from amplification-associated increases in epidermal growth factor receptor signaling is not necessarily dependent on the inactivation of PTEN/MMAC1.
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PMID:PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. 939 44


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