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)

In our earlier studies we have demonstrated that recombinant human interferon-alpha 2A (rHu-IFN-alpha 2A) inhibits hypothalamo-pituitary-adrenocortical (HPA) secretion following both peripheral and central administration. Furthermore, this effect is antagonized by mu-opioid receptor antagonists, suggesting transduction by this subtype of opioid receptors. In the present studies, we demonstrate that this effect is also observed with the hybrid recombinant preparation, rHu-IFN-alpha A/D, and a leucocyte-derived rat IFN-alpha preparation. The inhibitory effects on HPA activity were observed after intraperitoneal (i.p.) injections of rHu-IFN-alpha 2A (10(3) U), rHu-IFN-alpha A/D (10(4) U), and of Rat-IFN-alpha (1 and 10 U). Similar effects were observed with intracerebroventricular (i.c.v.) administration of all three IFN-alpha preparations. No increases in plasma concentrations of corticosterone were observed with doses of rHu-IFN-alpha A/D up to 10(6) U (i.p.) or 7 x 10(5) U (i.c.v.), but increases were found following i.c.v. administration of high doses of Rat-IFN-alpha (10(3) and 5 x 10(3) U). The inhibitory effects of all of the IFN-alpha preparations tested were antagonized by naloxone, but the stimulatory effects of 5 x 10(3) U Rat-IFN-alpha were not. Injections of rHu-IFN-alpha 2A (10(4) U i.p.) to urethane-anesthetized rats decreased the electrical activity of the majority of hypothalamic paraventricular nucleus neurons tested, including putative corticotropin-releasing factor-secreting neurons antidromically identified as projecting to the median eminence. These electrophysiological data suggest that the decreases in HPA activity evoked by IFN-alpha are mediated by a rapid inhibitory effect at the level of the corticotropin-releasing factor-secreting neurons. The sensitivity of many central nervous system effects of IFN-alpha to mu-receptor antagonists strongly suggests that the cytokine serves as an endogenous opioid agonist arising from the immune system. In support of this hypothesis we have shown that SH-SY5Y human neuroblastoma cells, differentiated with retinoic acid treatment to express predominantly mu-receptors, are sensitive to rHu-IFN-alpha 2A in vitro. This sensitivity took the form of a dose-dependent inhibition of forskolin-stimulated adenylyl cyclase activity. The data yielded an IC50 (95% confidence intervals) value of 7.93 (5.70-11.04) nM for this effect. Neither undifferentiated SH-SY5Y cells nor NG108-15 mouse neuroblastoma x rat glioma hybrid cells (expressing delta-receptors) were affected by rHu-IFN-alpha 2A.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of neural and neuroendocrine activity by alpha-interferon: neuroendocrine, electrophysiological, and biochemical studies in the rat. 800 70

The effect of intratumoral recombinant interferon gamma (rIFN-gamma) as adjuvant to open cytoreduction and external irradiation of 60 Gy on survival in adults with a newly diagnosed high-grade cerebral glioma was studied. The patients were randomised during surgery into the rIFN-gamma group (n = 14) or the control group (n = 17), and the latter received a subcutaneous reservoir of rIFN-gamma injections. Intratumoral rIFN-gamma was given three times a week for 4 weeks until radiotherapy, escalating the dose from 5 micrograms to 50 micrograms. Both groups received external whole-brain irradiation of 40 Gy and a local boost of 20 Gy. After radiotherapy, rIFN-gamma was continued with 50 micrograms twice a week up to 9 weeks. The patients received no chemotherapy. Intratumoral rIFN-gamma was tolerated well with transient fever only. There were 12 glioblastomas (GBs) in the control group and nine in the rIFN-gamma group with completed irradiation. The patients were followed clinically and by computerised tomography (CT) every third month until death. Tumour responses were seen in three interferon-treated (one still alive 45 months after operation) and in two conventionally treated patients. The progression of the tumour volumes on CT did not differ between the IFN-treated and control groups. There were no differences in the survival times. Median survival of the rIFN-gamma-treated patients was 54 weeks (95% CI 35-68) and of the control patients 55 weeks (95% CI 41-77). Intratumoral rIFN-gamma given in the study doses does not seem to inhibit tumour growth or improve the prognosis of patients with high-grade glioma.
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PMID:Randomised, controlled study of intratumoral recombinant gamma-interferon treatment in newly diagnosed glioblastoma. 801 25

The effect of mouse interferon alpha/beta (MuIFN alpha/beta) on the production of glycosaminoglycans (GAGs) by mouse glioma G-26 in vitro was evaluated. Two GAG species secreted extracellularly by the mouse glioma G-26 were isolated using cellulose acetate electrophoresis. They were identified as hyaluronic acid (HA) and chondroitin sulfate (CS) following enzymatic digestion with enzymes: hyaluronidase and chondroitinase ABC. Further characterization of CS by enzymatic digestion with specific chondroitinases for chondroitin 4-sulfate (CSA) and chondroitin 6-sulfate (CSC), revealed that the isolated CS was neither CSA nor CSC. Therefore, it may be either chondroitin sulfate B (CSB) (dermatan sulfate) or one of the 'chondroitin sulfate isomers' (D-H). The three day incubation of glioma G-26 cells with 8 x 10-8 x 10(4) U/ml of MuIFN alpha/beta resulted in a dose dependent inhibition of cell proliferation measured by 3H-thymidine incorporation and the MTT assay. The significant decrease of the CS (p < 0.008) but not the HA level, (measured densitometrically), was observed following 72 hours (hrs) incubation of G-26 cells with 8 x 10(3) U/ml of MuIFN alpha/beta (IFN treated cells: 0.03 +/- 0.007 integrated optical density (IOD); control cells: 0.07 +/- 0.01 IOD). The decreased CS production may be the underlying cause of IFN mediated inhibition of glioma cell proliferation.
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PMID:Interferon effect on glycosaminoglycans in mouse glioma in vitro. 805 39

Loss of genetic information from a number of specific regions of the genome has been documented in primary human gliomas. Recently loss of heterozygosity or nullizygosity of the IFN beta 1 gene has been found in glioblastomas. We used Restriction Fragment Length Polymorphism (RFLP) analysis in order to screen the frequency of the loss of this genes in glial tumors of malignancy grades I-IV. Nullizygosity for IFN beta 1 was detected in 8/30 (27%) of glioblastomas (malignancy grade IV) and loss of heterozygosity in a further two cases (7%). In total, 33% of these tumors lost least one copy of the IFN beta 1 gene. Among the 10 anaplastic gliomas (grade III), 2 (20%) showed loss of one copy of the gene which none of the 7 low grade gliomas (grades I or II) showed any evidence of loss of IFN beta 1 alleles. The loss of the IFN beta 1 gene would appear to be a late event associated with the development of an increasingly malignant phenotype in human gliomas and to be confined to gliomas of malignancy grade III or IV.
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PMID:Frequency of IFN beta 1 gene loss in 47 primary human gliomas. 810 98

Viral infection results in enhancement of HLA-class I expression in a number of cell types, including glial cells, which normally do not express these molecules. This enhancement may occur through a direct interaction between a viral component and the HLA-class I gene or indirectly through virus-induced soluble factors produced by infected cells. These include cytokines such as IFN-gamma, IFN-alpha/beta, and TNF-alpha, known to enhance class I expression. Measles virus (MV) infection of a human glioma cell line (U-105 MG) and of primary human umbilical vein endothelial cells enhances the expression of HLA-class I molecules on these cells. The enhancement of HLA-class I is dependent on infectious virus, as antibody-neutralized MV has no effect on class I expression. In this study, we demonstrate the presence of an HLA-class I-enhancing factor in supernatants from MV-infected cells. The supernatant class I-enhancing factor is not IFN-gamma, IFN-alpha, or TNF-alpha because MV-infected cells did not produce measurable levels of these cytokines as detected by immunoassay or polymerase chain reaction. In contrast, IFN-beta is produced by the infected cells and the supernatant class I-enhancing factor could be entirely neutralized by antibodies to IFN-beta, but not antibodies to IFN-alpha, TNF-alpha, or non-immune sera. Furthermore, preincubation of cells with neutralizing antibodies to IFN-beta prior to infection blocked MV enhancement of HLA-class I completely in the U-105 MG cells and by as much as 74% in the umbilical vein endothelial cells. The results of these experiments provide direct evidence that enhanced HLA-class I expression in MV-infected cells is mediated primarily by IFN-beta.
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PMID:Direct evidence that interferon-beta mediates enhanced HLA-class I expression in measles virus-infected cells. 824 64

The ethyl-N-nitrosourea-induced rat glioma N32 was treated with the mutagenic compound N-methyl-N'-nitro-N-nitrosoguanidine and the surviving cells cloned by limited dilution. Out of 20 clones tested 8 did not produce tumors subcutaneously even after challenge doses 3 log units above the minimal tumor dose for N32. All of 5 clones grew in a retarded manner intracerebrally but produced tumors in some animals. Preimmunizations with three of the rejected clones (tum-) gave protection against subcutaneous and intracerebral isografts of the unmutated N32. This effect could be enhanced if the cells used for immunizations were pretreated with interferon gamma (IFN gamma) for 48 h. If immunizations were started subsequent to challenge, only immunization with one of two tested tum- clones pretreated with IFN gamma induced significant rejection against intracerebral N32 isografts. Both N32 and its tum- clones were MHC class I positive and MHC class II negative. IFN gamma treatment enhanced the MHC class I expression with 20%-90% on the tum- clones and with 40% on N32. MHC class II expression could be induced on N32 cells after 7 days of IFN gamma treatment but not on any of the tum- clones tested. We conclude that the enhancing effect of IFN gamma treatment on tumor isograft rejection may depend on up-regulation of MHC class I but not of MHC class II. This investigation demonstrates that it is possible to induce rejection of weakly immunogenic intracerebral brain tumors by immunization with selected highly immunogenic tumor cell mutants. In conjunction with relevant cytokines, the cross-protective effect of these tum- variants might be further enhanced and serve as a model for immunotherapy against malignant human brain tumors.
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PMID:Immunization with mutagen-treated (tum-) cells causes rejection of nonimmunogenic rat glioma isografts. 851 54

Transmission electron microscopy was used to determine how immunogold labeling of PKC-alpha or -beta is modulated by the antitumor drug IFN (HuIFN alpha-2b) in the cytoplasm, membrane structures, and nucleus of rapidly dividing and confluent human glioma U-373 cells. Results showed that except for nuclear localization, there were no specific cytoplasmic organelles that PKC-alpha or -beta translocated to following HuIFN alpha-2b treatment. Electron micrographs of PKC-beta in proliferating cells depicted 1.34-fold more PKC-beta in the nucleus than in the cytoplasm and a 1-min HuIFN alpha-2b (500 units/ml) treatment transiently increased PKC-beta immunoreactivity in the cytoplasm (1.95-fold) and nucleus (1.97-fold). In confluent cells, incubation with HuIFN alpha-2b for 2 min significantly decreased cytoplasmic PKC-beta immunoreactivity by 37%, and no change was observed in nuclear PKC-beta labeling. PKC-alpha labeling in proliferating cells showed similar immunoreactivity in both control cytoplasm and nucleus. Treatment of proliferating cells with HuIFN alpha-2b for 2 min decreased PKC-alpha in the cytoplasm (59%) and nucleus (44%). In confluent cells, cytoplasmic PKC-alpha labeling decreased 59% at 1 min, 61% at 2 min, and 76% at 10 min of HuIFN alpha-2b treatment. Nuclear PKC-alpha decreased by 65% at 1 min, 80% at 2 min, and 62% at 10 min after HuIFN alpha-2b treatment. Western blots of total PKC-alpha in proliferating and confluent cells and PKC-beta in confluent cells showed similar results. However, Western blots of total PKC-alpha and -beta in proliferating cells did not demonstrate any significant changes in either PKC-alpha or -beta immunoreactivity following 1-min HuIFN alpha-2b treatment. These results suggest that treatment of proliferating U-373 cells with HuIFN alpha-2b for 1 min unfolds and exposes PKC-beta antigenic sites (hinge region) and increases in situ PKC-beta immunogold labeling.
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PMID:In situ effects of interferon on human glioma protein kinase C-alpha and -beta ultrastructural localization. 856 73

Oligodendrocytes (OLs) and their myelin membranes are the apparent injury targets in the putative human autoimmune disease multiple sclerosis. The basis for this selective injury remains to be defined. OLs in vitro have been shown to be susceptible to both tumor necrosis factor (TNF) and non-TNF-dependent immune effector mechanisms. The former involves initial nuclear injury (apoptosis); the latter, when mediated by activated T cells, involves initial cell membrane injury (lysis). In the current study, we determined whether human adult CNS-derived OLs could be protected from the above immune effector mechanisms by selected neurotrophic factors (CNTF, BDNF, NGF, NT-3, and NT-4/5) or cytokines demonstrated to protect from human or experimental autoimmune demyelinating diseases (beta-interferon [IFN], IL-10, and TGF-beta). Nuclear injury was assessed in terms of DNA fragmentation using a DNA nick-end-labelling technique; cell membrane injury was assessed by lactate dehydrogenase or chromium 51 release. MTT and cell counting assays were used to assess cell viability and cell loss, respectively. Amongst the neurotrophic factors and cytokines tested, only CNTF significantly protected the OLs from TNF-mediated injury. CNTF also protected the OLs from serum deprivation-induced apoptosis. CNTF, however, did not protect the OLs from injury induced by activated CD4+ T cells. CNTF also did not protect human fetal cortical neurons from serum deprivation or TNF-induced DNA fragmentation, nor did it protect the U251 human glioma cell line from DNA fragmentation induced by a combination of TNF and reduced serum concentration in the culture media. Our results indicate that potential protective effects of neurotrophic factors or cytokines on neural cell populations can be selective both for cell type involved and mechanism of immune-mediated injury. CNTF is the protective factor selective for nuclear-directed injury of OLs.
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PMID:Ciliary neurotrophic factor selectively protects human oligodendrocytes from tumor necrosis factor-mediated injury. 871 18

We have investigated the anti-tumor activity of ex vivo activated and expanded T cells which had been sensitized in vivo to one of two different syngeneic rat glioma cell lines; D74 or RT-2. Rats were sensitized by inoculation of irradiated tumor cells into each hind foot pad. After 10 days, the tumor-draining lymph node (DLN) from each popliteal region was excised and prepared as a single cell suspension. Tumor-DLN lymphocytes were next activated overnight in RPMI-1640 medium containing 10% fetal bovine serum (FBS), Bryostatin-1 (5 nM), ionomycin (1 microM), and 20 U human recombinant interleukin-2 (IL-2) per ml. Culture for seven days in RPMI-1640 supplemented with FBS and IL-2 resulted in approximately 100-fold expansion of the lymphocyte population. Both D74- and RT-2-sensitized T cells constitutively secreted tumor necrosis factor-alpha, and both lymphocyte populations produced comparable amounts of the cytokine when co-cultured with either glioma cell line. Neither D74- and RT-2-sensitized effectors constitutively secreted gamma-interferon (gamma-IFN), but both populations produced gamma-IFN when exposed to either glioma cell line in vitro. D74-sensitized T cells released significantly more gamma-IFN than the RT-2 DLN lymphocytes. In vitro Chromium-release assays indicated that RT-2-sensitized T cells were more cytotoxic for RT-2 targets than for the D74 line and that D74-sensitized effectors were also more cytotoxic for RT-2 targets. To assess in vivo therapeutic efficacy, rats who had been inoculated intradermally with RT-2 cells three days earlier received an intravenous injection of RT-2- or D74-sensitized DLN cells (10(6) cells/gram body weight) expanded after activation with Bryostatin-1 and ionomycin or an equal number of lymphokine-activated killer (LAK) cells. Tumor diameters were measured daily and revealed that injection of glioma-sensitized lymphocytes led to the elimination of tumor while treatment with LAK cells had no therapeutic benefit. These results indicate, that at least for these two glioma lines, gamma-IFN release, rather than in vitro cytotoxicity, was a better predictor for in vivo immunotherapeutic efficacy of the glioma-sensitized, expanded T cells.
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PMID:Ex vivo expansion of tumor-draining lymph node cells using compounds which activate intracellular signal transduction. II. Cytokine production and in vivo efficacy of glioma-sensitized lymphocytes. 904 60

Rat interferon beta (IFN beta) was cloned from a part of rat genomic DNA by the polymerase chain reaction (PCR) with reference to the nucleotide sequence data of a mouse IFN beta. The sequence result showed that the clone had 555 bp of open reading frame (ORF) which encoded a 184-amino acid polypeptide. Comparison of our data with those of mouse and human IFN beta revealed 86.7 and 67.6% homology at the nucleotide level, and 76.2 and 48.9% homology at the amino acid level, respectively. This ORF was inserted into an expression vector, pCAGGS, and COS-1 cells were then transfected with the plasmid encapsulated in cationic multilamellar liposomes. From the results of reverse transcription-PCR and cytopathic activity assay, this ORF expressed IFN beta in COS-1 cells. When the cultured cells of rat glioma cell line T9 were transfected with the plasmid, their growth was markedly suppressed due to the expression of rat IFN beta.
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PMID:Isolation and expression of rat interferon beta gene and growth-inhibitory effect of its expression on rat glioma cells. 912 38


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