Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this investigation is to elucidate antitumor activity of human interferon-beta (Hu IFN-beta) against nervous system tumors. The study of growth inhibition in vitro with IFN against a variety of human glioma and neuroblastoma cell lines showed a significant response with sensitive cell lines at the concentration of 1 X 10(3) IU/ml in the medium. With resistant cell lines, however, tumor cells were proliferated as control even at the concentration of 10(4) IU/ml. The activation of lymphocyte-mediated cytotoxicity was also studied. The microcytotoxicity test with AJ glioma cells as target was used to evaluate it. In this system, percentage of cytotoxicity was 33 +/- 10.0% by lymphocytes obtained from six healthy adult men and four patients with malignant glioma, and it was increased to 71 and 72% seven days after intravenous administration of IFN (daily dose 3 X 10(6) IU) for the treatment of gliomas. The results indicate that human IFN-beta is considered effective in the treatment of malignant gliomas.
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PMID:[Effect of interferon on malignant brain tumor]. 718 55

Deletions of 9p21-22, that frequently include the alpha-, beta- and omega-IFN gene cluster, are common in malignant diseases such as acute lymphocytic leukemia, malignant melanoma and malignant glioma. There is also evidence to support the role of a gene(s) on chromosome 9p21 in predisposition for familial malignant melanoma. Although initial studies implicated that the IFN genes could serve as tumor suppressor genes, there is now data, mainly based on estimations of minimum region of overlap for the deletions, indicating that the relevant tumor suppressor gene is located centromeric of the alpha-, beta-, omega-IFN gene cluster.
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PMID:Chromosome 9 short arm deletions in malignant diseases. 750 46

An established human astrocytoma cell line (T67) was shown to constitutively produce the proteinase inhibitor alpha 2 macroglobulin (alpha 2M). Interferon gamma (IFN gamma), a potent immunoregulatory lymphokine, was able to increase the synthesis of alpha 2M by these cells, as measured by ELISA on cell supernatants. The alpha 2M induction was also observed in other human glioma cell lines (T70 and ADF) and in human fetal astrocyte cultures following IFN gamma treatment. In T67 cells this effect was dose-dependent and the maximum (2.7-fold increase) was obtained with 2000 U/ml of IFN gamma. A corresponding enhanced alpha 2M mRNA accumulation was demonstrated by PCR and Northern blot techniques. Our results suggest an important role of alpha 2M during inflammatory and immune processes in the CNS. An increased release of alpha 2M following IFN gamma stimulation may allow the removal of the bulk of proteases released at the site of inflammation, strengthening at the same time the antigen presentation processes.
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PMID:Interferon gamma up-regulates alpha 2 macroglobulin expression in human astrocytoma cells. 751 32

This study evaluates cerebral entry of mouse interferon alpha/beta (MuIFN alpha/beta) or mouse interferon gamma (MuIFN-gamma) following continuous (3 day), subcutaneous infusion of normal or glioma bearing mice. The intracerebral C57BL/6 mouse glioma-26 (G-26) model was used at days 10-14 post tumor implant, the advanced stage of glioma progression as defined by histology and the median survival time (27 +/- 3.8 days). The infusion of horseradish peroxidase (HRP) in vivo at day 10 or 11 post glioma implant showed strong staining in the tumor bed indicating compromised blood-brain barrier (BBB). In addition, histochemistry with Bandeiraea simplicifolia isolectin B4 demonstrated the accumulation and/or activation of macrophage/microglia. The 3 day infusion of mice (day 11-14 post tumor implant) via subcutaneous (sc) osmotic micro-pumps with MuIFN alpha/beta (8x10(5) - 1.7x10(6) international units [IU]/ml) or with recombinant mouse interferon gamma (rMuIFN-gamma) (1x10(6) IU/ml) resulted in a low but detectable (1-5 IU/ml) cerebral level of IFN. The IFN levels in the blood (20-40 IU/ml) and brain, measured by assay of inhibition of viral cytopathic effect (CPE) or ELISA assay for MuIFN-gamma, showed no difference between normal and glioma bearing mice. The lipoxygenase (LO) activity (dioxygenase) of glioma tissue and contralateral control was evaluated in non-treated and MuIFN alpha/beta continuously (3 day) treated mice. The LO activity in glioma tissue was significantly higher (p < 0.05) than the contralateral control in non-treated mice. However, following sc MuIFN alpha/beta infusion the LO activity of glioma decreased to control level.
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PMID:Interferon entry through the blood-brain barrier in glioma and its effect on lipoxygenase activity. 752 Nov 51

Fas/APO-1 is a transmembrane protein of the nerve growth factor/TNF alpha receptor family which signals apoptotic cell death in susceptible target cells. We have investigated the susceptibility of seven human malignant glioma cell lines to Fas/APO-1-dependent apoptosis. Sensitivity to Fas/APO-1 antibody-mediated cell killing correlated with cell surface expression of Fas/APO-1. Expression of Fas/APO-1 as well as Fas/APO-1-dependent cytotoxicity were augmented by preexposure of human malignant glioma cells to IFN gamma and TNF alpha. Further, pretreatment with TGF beta 2, IL1 and IL8 enhanced Fas/APO-1 antibody-induced glioma cell apoptosis whereas other cytokines including TNF beta, IL6, macrophage colony-stimulating factor, IL10 and IL13 had no such effect. None of the human malignant glioma cell lines was susceptible to TNF alpha-induced cytotoxicity. Fas/APO-1 antibody-sensitive glioma cell lines (n = 5), but not Fas/APO-1 antibody-resistant glioma cell lines (n = 2), became sensitive to TNF alpha when co-treated with inhibitors of RNA and protein synthesis. Resistance of human glioma cells to Fas/APO-1 antibody-mediated apoptosis was mainly related to low level expression of Fas/APO-1 and appeared not to be linked to overexpression of the anti-apoptotic protooncogene, bcl-2. Given the resistance of human malignant glioma to surgery, irradiation, chemotherapy and immunotherapy, we propose that Fas/APO-1 may be a promising target for a novel locoregionary approach to human malignant glioma. This strategy gains support from the demonstration of Fas/APO-1 expression in ex vivo human malignant glioma specimens and from the absence of Fas/APO-1 in normal human brain parenchyma.
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PMID:Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. 752 90

Interstitial deletions of the short arm of chromosome 9 are associated with glioma, acute lymphoblastic leukemia, melanoma, mesothelioma, lung cancer, and bladder cancer. The distal breakpoints of the deletions (in relation to the centromere) in 14 glioma and leukemia cell lines have been mapped within the 400 kb IFN gene cluster located at band 9p21. To obtain information about the mechanism of these deletions, we have isolated and analyzed the nucleotide sequences at the breakpoint junctions in two glioma-derived cell lines. The A1235 cell line has a complex rearrangement of chromosome 9, including a deletion and an inversion that results in two breakpoint junctions. Both breakpoints of the distal inversion junction occurred within AT-rich regions. In the A172 cell line, a tandem heptamer repeat was found on either side of the deletion breakpoint junction. The distal breakpoint occurred 5' of IFNA2; the 256 bp sequenced from the proximal side of the breakpoint revealed 95% homology to long interspersed nuclear elements. One- and two-base-pair overlaps were observed at these junctions. The possible role of sequence overlaps, and repetitive sequences, in the rearrangement is discussed.
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PMID:Breakpoint junctions of chromosome 9p deletions in two human glioma cell lines. 752 63

The majority of human malignant glioma cells express Fas/APO-1 and are susceptible to Fas/APO-1 antibody-mediated apoptosis in vitro. The sensitivity of Fas/APO-1-positive glioma cell lines to Fas/APO-1 antibody-mediated killing correlates inversely with the constitutive expression of the antiapoptotic protooncogene bcl-2. Here we report that BCL-2 protein expression of human glial tumors in vivo correlates with malignant transformation in that BCL-2 immunoreactive glioma cells were more abundant in WHO grade III/IV gliomas than in grade I/II gliomas. Fas/APO-1 antibody-sensitive human glioma cell lines stably transfected with a murine bcl-2 cDNA acquired resistance to Fas/APO-1 antibody-mediated apoptosis. Forced expression of bcl-2 also attenuated TNF alpha-mediated cytotoxicity of glioma cell lines in the presence of actinomycin D and cycloheximide and conferred partial protection from irradiation and the cancer chemotherapy drugs, cisplatin and BCNU. Preexposure of the glioma cell lines to the cytokines, IFN gamma and TNF alpha, which sensitize for Fas/APO-1-dependent killing, partially overcame bcl-2-mediated rescue from apoptosis, suggesting that multimodality immunotherapy involving cytokines and Fas/APO-1 targeting might eventually provide a promising approach to the treatment of human malignant gliomas.
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PMID:Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. 753 58

This study investigated the role of activated macrophages (M phi) in nitric oxide (NO) production and the tumoricidal effect of NO on glioma cells. Induced peritoneal M phi were prepared 6 days following the injection of thioglycollate broth into C3H/He N (H-2 kappa) mice. M phi were activated in vitro recombinant human interferon-gamma (IFN gamma) and lipopolysaccharide (LPS) into the culture medium of the elicited M phi. Two kinds of murine malignant glioma cell lines, RSV-M glioma (H-2 kappa) and VM-glioma (H-2b) were used as targets. P815 mastocytoma cells (H-2d) were used as a control target, since they are insensitive to tumor necrosis factor-alpha, but susceptible to NO derived from M phi. L-arginine-depleted medium was used to inhibit NO-mediated cytocidal activity against tumor cells. Cytotoxicity was assayed at various effector-to-target ratios using an admixture of M phi and 1.5 x 10(4) 125I-labeled target cells 48 hours following co-culture. NO was measured in culture medium using Griess reagent, and the concentration of NO was expressed as mu mol/ml NaNO2. Peritoneal M phi induced only 10% and 15% lysis of RSV-M glioma and VM glioma cells, respective, and LPS augmented this killing activity of M phi to a maximum of 1.2 to 1.4 fold in a dose-dependent manner with dosages from 1 to 50 ng/ml. LPS demonstrated a synergistic action on M phi-mediated cytotoxicity 4 hours following pretreatment with IFN gamma. Alternatively, low doses of IFN gamma alone had no enhancing effect on M phi tumoricidal activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Role of nitric oxide produced by activated macrophages in their cytocidal activity against glial tumor cells]. 777 2

The goal of this study was to determine the antitumor activity and toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus recombinant interferon-alpha (IFN-alpha) in patients with recurrent glioma. As single agents, both BCNU and IFN-alpha can cause tumor regression in patients with recurrent glioma. In vitro studies suggest synergy between the two agents. Thirty-five patients in whom computerized tomography (CT) or magnetic resonance (MR) evidence was obtained of progressive astrocytoma, oligoastrocytoma, or oligodendroglioma received recombinant IFN-alpha 2a (12 x 10(6) U/m2 intramuscularly) on Days 1 through 3 and BCNU (150 mg/m2 intravenously) on Day 3 of each 6-week cycle. All patients had tumor progression despite radiation therapy and had received no prior chemotherapy. Response was assessed by CT or MR evidence and by neurological examination while the patients were on a regimen of stable or decreasing doses of corticosteroids. All patients could be evaluated for response and toxicity. Twenty-nine percent of the patients demonstrated objective tumor regression; 37% remained stable for more than 6 months and 25% were stable for less than 6 months. The median duration of response to IFN-alpha and BCNU was 9.9 months and the median survival for all patients was 13.3 months. Toxicity consisted primarily of moderate myelosuppression, venous irritation, vomiting, flulike symptoms, and transient reversible exacerbation of underlying neurological symptoms. The use of BCNU plus IFN-alpha is a safe, active regimen in the treatment of patients with recurrent glioma who have failed to respond to prior radiation therapy. The contribution of IFN to the antitumor activity observed in this study compared with that previously described with BCNU alone cannot be assessed from this trial.
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PMID:Phase II evaluation of recombinant interferon alpha and BCNU in recurrent glioma. 786 Dec 21

Little information exists regarding which glioma cells are able to escape immune system detection and progress within the host. In order to elucidate some of the mediators which facilitate the growth and spread of glioma cells, the expression of cytokines, TNF-alpha, IL-6, gamma-IFN, IL-10, and GM-CSF, within 12 human glioma specimens was investigated by the polymerase chain reaction. The twelve patients with malignant glioma were categorized into a localized (n = 4) and an invasive glioma (n = 8) groups, mostly glioblastoma multiforme, based upon the CT and MRI scans. We examined the correlation between specific cytokine gene expression and the clinical category of each patient. The results showed that while IL-10 mRNA transcripts were expressed in most of the tumors from the invasive glioma group (7/8), they were not expressed in tumors from the localized group. On the other hand, gamma-IFN gene expression was more frequent in tumors from the localized group (3/4 vs 1/8 from the invasive group). The mRNA transcripts of IL-6 and GM-CSF were more frequently expressed in tumors from the localized group. No consistent pattern was seen in TNF-alpha gene expression between the two groups. Among the five cytokines studied, IL-10 mRNA was selectively expressed within invasive gliomas compared to less malignant, localized glioma group. Our results demonstrate specific cytokine mRNA profiles in glioma patients, which might have prognostic significance for immunotherapy.
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PMID:Selective expression of interleukin-10 gene within glioblastoma multiforme. 795 24


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