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)

Despite the development of numerous vectors for gene transfection to gliomas, patient survival length remains unaffected in clinical trials. For glioma gene therapy to be successful, the extent of gene transfer to the solid tumor tissue has to be high. In the present work we review some of the vector types and strategies so far utilized in experimental and clinical glioma gene therapy. Since gene transfer efficacy into solid glioma tissue is unknown for many vectors, we studied the gene transfer efficacy into multicellular spheroids derived from a human glioma cell line GaMg as well as into spheroids derived from human glioma biopsies (glioblastoma multiforme, GBM). A replication deficient retroviral vector from the Liz 9 packaging cell line was used for transfer of the bacterial beta-galactosidase lacZ gene into the target tissue. Gene transfer was obtained by adding medium containing virus from the producer cells to the target tissue. The experiments were also conducted with EGF (epidermal growth factor) added to the medium. The data show that the transfection rate ranged from 0-4.5% where the transfection efficacy was higher in spheroids after the addition of EGF. Most of the transfected cells were found at the surface, but transfected cells could also be observed in the center of the spheroids. We conclude that using this vector system, the transfection efficacy was low, even if the number of replicating cells was increased by adding EGF. The findings are consistent, and may partly explain, the lack of effect using this vector system during in vivo studies.
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PMID:Retroviral transfection of the lacZ gene from Liz-9 packaging cells to glioma spheroids. 1057 26

In recent years gene therapy has evolved as a new treatment for brain tumors, where genetically engineered cells can be used to deliver specific substances to target cells. However, clinical success has been limited due to insufficient gene transfer, lack of prolonged gene expression, and immunorejection of producer cells. These obstacles may be overcome by encapsulating producer cells into immunoisolating substances such as alginate. This may provide a stable in situ delivery system of specific proteins, which can interfere with tumor growth and differentiation. This article represents a fundamental study describing the in vitro and the in vivo behavior of alginate-encapsulated producer cells. The viability and cell cycle distribution of encapsulated NIH 3T3 cells was studied by confocal laser scanning microscopy (CLSM) and by flow cytometry. The CLSM study showed a high viability of the encapsulated NIH 3T3 cells during 9 weeks in culture. The flow cytometric analysis revealed a change in cellular ploidy after 1 week in culture, with normalization in ploidy after 3 and 9 weeks. The production of the bacterial E. coli beta-galactosidase in alginate-encapsulated BT4CnVlacZ cells was studied by x-gal staining, and the cells expressed prolonged beta-galactosidase activity. H528 hybridoma cells producing monoclonal antibodies (mAbs) against the human epidermal growth factor receptor (EGFR) were encapsulated in alginate, and the mAb release was determined. The release of mAbs stabilized around 400 ng/ml/h after 12 days in vitro. To actually demonstrate that alginate-encapsulated H528 cells potentially inhibit a heterogeneous glioma cell population, cell migration from human GaMg glioma spheroids was studied during stimulation with EGF in the presence of encapsulated H528 cells. The migration in vitro was totally inhibited in the presence of H528 encapsulated cells. Alginate beads with H528 cells were also implanted into rat brains, and after 9 weeks the distribution of mAbs within the brain was studied by immunohistochemistry. It is shown that the alginate entrapped H528 cells produce mAbs inside the brain for prolonged periods and that the mAbs are distributed within all CSF compartments. Encapsulated producer cells represent a potential delivery system for specific proteins to brain tumors. Different producer cells may be encapsulated in alginate to target phenotypic features and microenvironmental factors, which may influence the progressive growth of brain tumors.
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PMID:Alginate-encapsulated producer cells: a potential new approach for the treatment of malignant brain tumors. 1120 64

The somatostatin receptor subtype sst2A is highly expressed, non-mutated and functionally active in gliomas. After stimulation of cultivated human U343 glioma cells with somatostatin, octreotide (sst2-, sst3- and sst5-selective peptide agonist) or the sst2-selective non-peptide agonist L-054,522 multiple signal transduction pathways are induced: elevated cAMP levels are reduced, protein tyrosine phosphatases (especially SHP2) are activated and mitogen-activated protein kinases are inhibited. Stimulation of the phosphatases resulted in dephosphorylation of activated receptors for EGF and PDGF (epidermal and platelet-derived growth factor), and as a consequence the mitogen-activated protein kinases ERK 1 and 2 (p42/p44) were de-phosphorylated in co-stimulation experiments. Furthermore, somatostatin or sst2-selective agonists reduced EGF-stimulated expression of the AP-1 complex (c-jun/c-jun) on the transcriptional and translational level. These experiments show that the interaction of stimulatory and inhibitory receptors are important mechanisms for the regulation of signal cascades and gene expression.
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PMID:Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells. 1122 55

In various cell types, the neuro- and endocrine peptide somatostatin induces inhibitory and anti-secretory effects. Since somatostatin receptors, especially of the subtype sst2A, are constantly over-expressed in gliomas, we investigated the influence of somatostatin and the receptor subtype-selective peptide/non-peptide agonists octreotide and L-054,522 on the secretion of the most important angiogenesis factor produced by gliomas, vascular endothelial growth factor (VEGF). Cultivated cells from solid human gliomas of different stages and glioma cell lines secreted variable amounts of VEGF, which could be lowered to 25% to 80% by co-incubation with somatostatin or sst2-selective agonists (octreotide and L-054,522). These effects were dose-dependent at nanomolar concentrations. Stimulation with different growth factors (EGF, bFGF) or hypoxia considerably increased VEGF production over basal levels. Growth factor-induced VEGF synthesis could be suppressed to <50% by co-incubation with somatostatin or an sst2-selective agonist; this was less pronounced in hypoxia-induced VEGF synthesis. The effects were detected at the protein and mRNA levels. These experiments indicate a potent anti-secretory action of somatostatin or sst2 agonists on human glioma cells that may be useful for inhibiting angiogenesis in these tumors.
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PMID:Somatostatin inhibits the production of vascular endothelial growth factor in human glioma cells. 1130 89

High levels of growth factors and their receptors have been demonstrated in human tumors. Gliomas and meningiomas are characterized by overexpression of epidermal growth factor receptor (EGF-R). Ior egf/r3, is a neutralizing murine monoclonal antibody (MAb) against EGF-R, and was generated at the Cuban Institute of Oncology. The antibody recognizes EGF-R with high affinity, inhibiting tyrosine kinase activation. A clinical trial was conducted in brain tumor patients to evaluate toxicity, immunogenicity, and clinical benefit of escalating doses of the antibody. Nine patients with histologically confirmed gliomas or meningiomas, who had active or recurrent disease after receiving conventional treatment, received four intravenous doses of ior egf/r3. Total dosages ranged from 160 to 480 mg. As inclusion criteria, radioimmunoscintigraphy with the same MAb labeled with 99mTechnetium (99mTc) was performed. Immune response against the murine antibody was also evaluated. After four doses of ior egf/r3 MAb, no significant toxicity was found, except in one patient who developed a grade 4 allergic adverse event. This reaction was probably related with previous sensitization to the same MAb and the development of human anti-mouse antibodies (HAMA) response. Despite no major objective antitumor responses, eight patients had stable disease on the 6-month evaluation, and two patients remain alive after four years of MAb therapy.
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PMID:Phase I clinical evaluation of a neutralizing monoclonal antibody against epidermal growth factor receptor in advanced brain tumor patients: preliminary study. 1139 32

Four different types of radiolabelled dextranated EGF were added to spheroids consisting of the human glioma cells U-343MGaCl2:6. Binding was analysed both in the peripheral well-nourished regions and in the deeper regions containing mainly quiescent cells. The substances had different molecular weights, and they were characterized regarding hydrophilic properties and isoelectric points. Two of the analysed conjugates, 125I-EGF-dextran (CDAP) and 125I-EGF-allyldextran-BSH, gave very low 125I binding in the deeper regions even after 24 h of incubation while better binding in these regions was found for 125I-EGF-dextran-DTPA, 125I-EGF-allyldextran and for the reference substance 125I-EGF. The molecular weight seemed not to be of major importance for the binding properties and there were no clear relationships between binding and the hydrophilic properties or the isoelectric point values. The obtained differences could not be explained by differences in molecular weight or easily measured physicochemical parameters such as hydrophilic properties or isoelectric point values. Thus, other explanations must be found.
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PMID:Effects of dextranation on the uptake of peptides in micrometastases: studies on binding of EGF in tumor spheroids. 1139 48

The promoter of the early growth response gene (Egr-1) has been described to be activated by ionizing radiation, and it seems to be clear that this process involves different mitogen activated protein (MAP) kinases, dependent on the specific cell type examined. However, early steps leading to activation of the corresponding pathways and thus to overexpression of Egr-1 are not well understood. In this study, deletion mutants of the 5' upstream region of the Egr-1 gene were generated which allowed us to correlate the radiation-induction of the Egr-1 promoter in U87 glioma cells to five serum response elements. Based on the data shown, a possible role of two cAMP responsive elements for radiation-dependent promoter regulation could be ruled out. On the basis of activator/inhibitor studies applying fetal bovine serum, EGF, PD98059, anisomycin, SB203580, forskolin and wortmannin, it could be demonstrated that in U87 cells the ERK1/2 and potentially SAPK/JNK, but not the p38MAPK/SAPK2, pathway contribute to the radiation-induction of Egr-1 promoter. In addition, it was observed that irradiated cells secrete a diffusible factor into the culture media which accounts for the radiation-induced promoter upregulation. By blocking growth factor receptor activation with suramin, this effect could be completely abolished.
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PMID:Early growth response-1 gene (Egr-1) promoter induction by ionizing radiation in U87 malignant glioma cells in vitro. 1178 28

Chinese hamster ovary (CHO) cells transfected with the wild-type gene for the human epidermal growth factor-receptor (EGFR) and expressing the receptor in their cell membrane are, together with the receptor negative parent CHO cells, an interesting model system for experimental EGFR-targeting tumour therapy. Comparisons of effects on nearly identical cells with and without receptors can be made. The main purpose of this work was to compare the internalisation and retention of the radioactivity delivered as 125I-EGF or 125I-EGF-dextran in transfected cells (called CHO-EGFR), and human glioma cells U-343 which naturally express wild-type EGFR. We found that radioactivity delivered as 125I-EGF-dextran was retained intracellularly by both cell types to a higher degree than radioactivity delivered as 125I-EGF. Prolonging the cellular exposure time for 125I-EGF-dextran considerably increased postincubation intracellular retention in both cell types. No major differences between the two EGFR expressing cell lines were found and, based on the results in this work, CHO-EGFR cells seem an adequate model for experiments with agents targeting the EGF-receptor.
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PMID:Internalisation and retention of EGF-dextran associated radioactivity in transfected Chinese hamster ovary cells expressing the human EGF-receptor. 1195 4

Liposomes are of interest as drug delivery tools for therapy of cancer and infectious diseases. We investigated conjugation of epidermal growth factor, EGF, to liposomes using the micelle-transfer method. EGF was conjugated to the distal end of PEG-DSPE lipid molecules in a micellar solution and the EGF-PEG-DSPE lipids were then transferred to preformed liposomes, either empty or containing the DNA-binding compound, water soluble acridine, WSA. We found that the optimal transfer conditions were a 1-h incubation at 60 degrees C. The final conjugate, (125)I-EGF-liposome-WSA, contained approximately 5 mol % PEG, 10-15 EGF molecules at the liposome surface, and 10(4) to 10(5) encapsulated WSA molecules could be loaded. The conjugate was shown to have EGF-receptor-specific cellular binding in cultured human glioma cells.
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PMID:Development of EGF-conjugated liposomes for targeted delivery of boronated DNA-binding agents. 1212 Nov 28

Much data about genetic imbalances in tumors have been accumulated by comparative genomic hybridization (CGH). In order to distinguish between significantly and coincidentally involved regions in glioma by means of a meta-analysis, we summarized and analyzed the CGH results of 509 cases published in 26 reports between 1992 and 2001. The expansion of all aberrations to the 850-band level impressively visualized distinct patterns in astrocytoma, oligodendroglioma, and ependymoma as well as loci of frequent aberrations. For example, in astrocytoma the frequency of gains culminated at 7p12, 8q24.1, and 12q13-q15 (the loci of EGF-R, C-MYC and CDK4, respectively) and losses at 9p21 (the locus of p15 and p16) and 10q23.3 where PTEN resides. Most chromosomes were variably prone to copy number changes at different scales of aberrations. At the whole chromosome level the analysis showed +7, -10 in astrocytoma and +9, +18 in ependymoma, but +20q, -9p in astrocytoma and +1q, -22q in ependymoma at the p-q arm level. Furthermore, we could confirm the correlation between the average number of copy alterations per patient (average number of copy alterations [ANCA] index) and malignancy for astrocytoma in a refined graduation as well as for oligodendroglioma. As a new parameter, the average number of affected GTG-bands per patient (average number of affected GTG bands [ANAG] index) showed an even more striking correlation with the World Health Organization grade for gains and losses.
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PMID:Comparative genomic hybridization in glioma: a meta-analysis of 509 cases. 1212 99


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