Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mongrel adult albino female rats with multiform glioblastoma transplanted to the right cerebellar hemisphere were given subcutaneous injections of 8 mg/kg of a serotonin-creatine sulphate solution beginning with the 3rd and to the 28th postoperative days. Rats with a tumor inoculated at the same periods and given injections of a physiological saline solution served as controls. The injection of serotonin leads to a significant increase in the survival of rats by 20% as compared to the survival of rats in the control group, but practically has no effect on the life span of sick animals. Consequently, serotonin either produces an antineoplastic effect in which case the animals do not contract the disease, or it has no effect on the tumor so that the animals die of the developing tumor. Study of the tryptophan content in the neoplasm and the 5-OIAA content in urine provides evidence of a disturbed serotonin synthesis and metabolism in these neoplasms.
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PMID:[Effect of serotonin on the viability of rats with transplanted glioblastoma multiforme]. 21 16

We have been studying the role of human cytomegalovirus (HCMV) as a potential cofactor in human immunodeficiency virus (HIV)-related disease. The clinical relevance of HCMV is highlighted by the fact that it is a principal viral pathogen in patients with AIDS and is known to infect the same cells as HIV. In this study, we focused on the molecular interactions between HIV and HCMV in human fibroblasts and in the human glioblastoma/astrocytoma-derived cell line U373 MG, cells which can be productively infected by both viruses. Because these cells are CD4-, we used HIV pseudotyped with a murine amphotropic retrovirus as described previously (D. H. Spector, E. Wade, D. A. Wright, V. Koval, C. Clark, D. Jaquish, and S. A. Spector, J. Virol. 64:2298-2308, 1990). Initial studies showed that when cells were preinfected with HIV (Ampho-1B) for 5 days and then superinfected with HCMV, HIV antigen production dropped significantly in the coinfected cells but continued to rise in cells infected with HIV (Ampho-1B) alone. HCMV production, however, was unaffected by the presence of HIV. Further analysis showed that HIV steady-state RNA levels and gag and env protein production were also inhibited in the presence of HCMV. The transcriptional inhibition of HIV was particularly surprising in view of the previous results of several other laboratories as well as our own that HCMV infection stimulates HIV long terminal repeat-chloramphenicol acetyltransferase (LTR-CAT) expression in transient expression assays. To investigate this further, we transfected the HIV LTR-CAT construct into either uninfected cells or cells which had been preinfected with HIV. The cells were infected with HCMV 24 h posttransfection and assayed for CAT gene expression at 48 h after HCMV infection. Although there was some stimulation of the LTR-CAT in cells that were dually infected by HIV and HCMV, it was 16-fold less than that in the cells infected only with HCMV. This suggests that in the presence of the HIV infection, the stimulation of the HIV LTR-CAT gene by HCMV is significantly reduced. Experiments with UV-irradiated HCMV and the HCMV DNA polymerase inhibitor ganciclovir showed that HCMV transcription is necessary for the reduction in HIV production to occur; however, replication of the HCMV genome or any events which take place after DNA replication are not necessary. These results, coupled with the observation that inhibition is usually first seen between 8 and 24 h after HCMV infection, suggest that an HCMV early protein is involved in repression of HIV.
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PMID:Human cytomegalovirus inhibits human immunodeficiency virus replication in cells productively infected by both viruses. 165 86

Interferon-gamma-induced tryptophan metabolism of human macrophages was compared to ten human neoplastic cell lines of various tissue origin and to normal dermal human fibroblasts. Tryptophan and metabolites were determined in supernatants of cultures, after incubation for 48 h, by high-performance liquid chromatography with ultraviolet and fluorescence detection. With the exception of two cell lines (Hep G 2, hepatoma and CaCo 2, colon adenocarcinoma) in all of the ten other cells and cell lines tryptophan degradation was induced by interferon-gamma. Five of these ten formed only kynurenine (SK-N-SH, neuroblastoma; T 24, J 82, bladder carcinoma; A 431, epidermoid carcinoma; normal dermal fibroblasts), three formed kynurenine and anthranilic acid (U 138 MG, glioblastoma; SK-HEP-1, hepatoma; A 549, lung carcinoma). Only one line, A 498 (kidney carcinoma) showed the same pattern of metabolites as macrophages (kynurenine, anthranilic acid and 3-hydroxyanthranilic acid). Interferon-gamma regulated only the activity of indoleamine 2,3-dioxygenase. All other enzyme activities detected were independent of interferon-gamma, as shown by the capacity of the cells to metabolize L-kynurenine or N-formyl-L-kynurenine. Increasing the extracellular L-tryptophan concentration resulted in a marked induction of tryptophan degradation by macrophages. Contrarily, a significant decrease of the tryptophan degrading activity was observed when the extracellular L-tryptophan concentration was increased 2-fold with SK-N-SH, T 24 and J 82, 4-fold with A 431 and A 549 and 10-fold with U 138 MG and SK-HEP-1. The activity was unaffected by extracellular L-tryptophan with dermal fibroblasts and A 498. Though interferon-gamma was the most potent inducer of tryptophan metabolism, interferon-alpha and/or -beta showed small but distinct action on some of the cells. In all cells which reacted to interferon-gamma by enhanced expression of class I and/or class II major histocompatibility complex antigens tryptophan degradation was also inducible. These results demonstrate that induction of indoleamine 2,3-dioxygenase is a common feature of interferon-gamma action, that the extent of this induction is influenced by extracellular L-tryptophan concentrations and that indoleamine 2,3-dioxygenase is the only enzyme in the formation of 3-hydroxyanthranilic acid from tryptophan which is regulated by interferon-gamma.
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PMID:Characteristics of interferon induced tryptophan metabolism in human cells in vitro. 250 Sep 76

Synthesis and metabolism of the epidermal growth factor (EGF) receptor are extensively regulated to modulate cellular responses to ligand. To study regulation of EGF receptor gene expression, the 5' region of the gene was isolated from a human placental genomic library. A 5' proximal 1.1-kilobase fragment (-1100 to -19 relative to the ATG translation start site) and subfragments of this were subcloned in both forward and reverse orientations into the luciferase expression vector pSVOAL delta 5' and transfected into human cell lines. Luciferase activity was stimulated by treatment of transfected HeLa cells with EGF, 12-O-tetradecanoylphorbol 13-acetate (TPA), (Bu)2 cAMP, retinoic acid, and dexamethasone. Deletion analysis indicated full retention of activity after removal of the -1100 to -485 region (-485 to -19 fragment), but a 5-fold reduction in activity on removal of the -485 to -153 region (-153 to -19 fragment). Despite a reduction in basal activity, the proximal 134-basepair fragment retained responses to all inducers. Additivity was observed in response to maximal concentrations of TPA plus retinoic acid and of TPA plus (Bu)2 cAMP; the response to a combination of four inducers exceeded that to the RSV-LTR strong promoter. Differences in stimulated responses were observed in various recipients, with hepatoma HepG2 cells lacking responses to (Bu)2 cAMP and glioblastoma T98G cells lacking responses to EGF and TPA. These results indicate that a 134-basepair DNA fragment closely adjacent to the translation start site contains elements responsible for directing basal and stimulated expression of the EGF receptor gene.
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PMID:Regulation of epidermal growth factor receptor gene expression. 254 Apr 31

As an in vitro model for human cerebral toxoplasmosis, we analysed the interaction between glioblastoma cells, Toxoplasma and Toxoplasma antigen-specific T-helper cells. We established 46 different human CD4+ T-cell clones from four different donors. All T-cell clones responded to Toxoplasma antigen derived from three different Toxoplasma strains. We found that the supernatants of 44 clones induced toxoplasmostasis in glioblastoma cells. The anti-parasitic effector mechanism activated in glioblastoma cells by T-cell supernatants was the induction of the tryptophan-degrading enzyme indolamine 2,3-dioxygenase. Enzyme induction, as well as the anti-parasitic effect, was blocked by a monoclonal antibody directed against interferon-gamma (IFN-gamma), and the addition of L-tryptophan to the cultures completely blocked the anti-parasitic effect induced by T-cell supernatants. The supernatants from two of the 46 established T-cell clones (3A22 and 1A15) were unable to induce indolamine 2,3-dioxygenase activity or, as expected, toxoplasmostasis in glioblastoma cells. We further analysed the supernatants from these two clones, and found that they contained large amounts of IL-4 and no, or only limited amounts of, IFN-gamma. We therefore conclude that Toxoplasma-antigen is able to activate T-helper type 1 (Th1)- and Th2-like human T cells, and only IFN-gamma-producing cells are capable of inducing anti-parasitic effector mechanisms.
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PMID:Establishment of T-helper type 1- and T-helper type 2-like human Toxoplasma antigen-specific T-cell clones. 759 Aug 86

Interferon-gamma (IFN-gamma) is a potent immune regulatory cytokine and is, in addition, involved in the induction of antiparasitic effector mechanisms in different cell types. The first step of IFN-gamma action is its binding to a specific receptor. Furthermore, it has been shown that IFN-gamma binds with a great affinity to the heparin-like structure of heparan sulfate, which is localized in basement membranes and on cell surfaces. In this study, we analyze the effect of heparin and heparan sulfate on three different IFN-gamma-mediated activities inducible in human glioblastoma cells (87HG31 and 86HG39). We find firstly that heparin is able to inhibit IFN-gamma-mediated induction of major histocompatibility complex (MHC) class II antigen expression on 87HG31 cells, an effect which can be abrogated by protamine. Secondly, we show that heparin inhibits the IFN-gamma-induced toxoplasmostasis within 86HG39 cells in a dose-dependent fashion, and thirdly that heparin inhibits the IFN-gamma-mediated induction of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase. In contrast to IFN-gamma-induced effects, the activity of other cytokines, such as interleukin (IL)-1, IL-2 and IL-6, is not influenced by heparin. The possible mechanism of heparin-induced inhibition of IFN-gamma is discussed.
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PMID:Heparin inhibits the antiparasitic and immune modulatory effects of human recombinant interferon-gamma. 770 97

Activation of the immune system which occurs in inflammatory disease leads to parallel increases in pterin synthesis and increased production of neuroactive L-tryptophan metabolites. Several model systems were studied to determine whether pterins, which are cofactors for hydroxylation reactions, could be required in the oxidative kynurenine pathway of L-tryptophan degradation. Treatment of mice with interferon-gamma increased L-tryptophan metabolism without any corresponding change in tissue biopterin concentrations. Cytokine-treated human fibroblasts, macrophages and glioblastoma cells all showed increases in kynurenine production, which were completely independent of pterin synthesis. When pterin synthesis de novo was blocked, either by an inhibitor of GTP cyclohydrolase or because of a genetic deficiency of one of the enzymes of the pathway of pterin biosynthesis, cytokine-stimulated increases in tryptophan metabolism were unaffected. Furthermore, increasing intracellular tetrahydrobiopterin concentrations by treating cells with sepia-pterin also had no effect on markers of tryptophan metabolism. Therefore, both normal and cytokine-stimulated L-tryptophan metabolism appears to be completely independent of pterin biosynthesis.
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PMID:Induction of pterin synthesis is not required for cytokine-stimulated tryptophan metabolism. 824 Feb 55

IFN-gamma induces the production of N-formyl-kynurenine from L-tryptophan in various cell types by the induction of the enzyme indoleamine 2,3-dioxygenase (IDO). The IFN-gamma induced IDO activity in the glioblastoma cell line 86HG39 and cells of clone 2D9 derived from this cell line was found to be greater than that in Hela cells and U373MG cells. Consequently 2D9 cells were used in all subsequent experiments. The determination of kynurenine in the supernatant of IFN-gamma activated cells was performed photometrically using a microplate reader. It was found that the amount of kynurenine produced was directly proportional to the amount of IFN-gamma used to activate cells. The detection limit for IFN-gamma of this assay was 20 U/ml. The induction of L-tryptophan degradation was specific for IFN-gamma since neither IFN-alpha, IFN-beta, IL-1, IL-2, IL-6, GM-CSF nor TNF alpha induced the production of detectable amounts of kynurenine by 86HG39 and 2D9 cells. Furthermore, a mab directed against IFN-gamma was able to completely block the IFN-gamma induced IDO activation. This bioassay was used to determine the IFN-gamma content of supernatants harvested from toxoplasma antigen specific human T cell lines and clones. This assay gave reproducible results which correlated well with the IFN-gamma content detected in the same samples using a commercially available ELISA kit. Furthermore in the case of T cell supernatant stimulated 2D9 cells a mab directed against IFN-gamma was able to completely block IDO induction. We conclude that the measurement of kynurenine production induced by IFN-gamma can be used to determinate IFN-gamma content. This is a simple bioassay which can be performed with standard laboratory equipment.
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PMID:A new, simple, bioassay for human IFN-gamma. 828 93

In the course of human toxoplasmosis central nervous system involvement often occurs. As a model for toxoplasma growth within human brain cells the proliferation of Toxoplasma gondii strain BK within the human glioblastoma cell line 86HG39 was analysed. We found that 86HG39 cells support the growth of toxoplasma similar to human monocyte derived macrophages and in contrast to human monocytes. The growth of Toxoplasma gondii within interferon gamma (IFN gamma) treated 86HG39 cells is reduced due to toxoplasmostasis and not due to toxoplasmocide effects. The mechanism of IFN gamma induced toxoplasmostasis was also investigated. It was found that IFN gamma did not induce O2- production and/or nitrite oxide production, and inhibitors of O2- and NO2- did not influence IFN gamma induced toxoplasmostasis. In contrast, the supplementation of L-tryptophan to the culture medium completely abolished the IFN gamma effect. We therefore conclude that the induction of L-tryptophan degradation in 86HG39 cells by IFN gamma, possibly by activation of the indoleamine-2,3-dioxygenase, is responsible for the IFN gamma induced toxoplasmostasis within the glioblastoma cell line.
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PMID:Induction of toxoplasmostasis in a human glioblastoma by interferon gamma. 838 36

Accumulation of quinolinic acid and L-kynurenine occurs in the brain and/or blood following immune activation, and may derive from L-tryptophan following induction of indoleamine 2,3-dioxygenase and other kynurenine-pathway enzymes. In the present study a survey of various cell lines derived from either brain or systemic tissues showed that, while all cells examined responded to interferon-gamma by increased conversion of L-[13C6]tryptophan into L-kynurenine (human: B-lymphocytes, neuroblastoma, glioblastoma, lung, liver, kidney; rat brain: microglia, astrocytes and oligodendrocytes), only macrophage-derived cells (peripheral-blood mononuclear cells; THP-1, U-937) and certain liver cells (SKHep1) synthesized [13C6]quinolinic acid. Tumour necrosis factor-alpha enhanced the effects of interferon-gamma in THP-1 cells. Norharmane, 6-chloro-DL-tryptophan and 4-chloro-3-hydroxyanthranilate attenuated quinolinic acid formation by THP-1 cells with IC50 values of 51 microM, 58 microM and 0.11 microM respectively. Norharmane and 6-chloro-DL-tryptophan attenuated L-kynurenine formation with IC50 values of 43 microM and 51 microM respectively, whereas 4-chloro-3-hydroxyanthranilate had no effect on L-kynurenine accumulation. The reductions in L-kynurenine and quinolinic acid formation are consistent with the reports that norharmane is an inhibitor of indoleamine 2,3-dioxygenase, 6-chloro-DL-tryptophan is metabolized through the kynurenine pathway, and 4-chloro-3-hydroxyanthranilate is an inhibitor of 3-hydroxyanthranilate 3,4-dioxygenase. These results suggest that many tissues may contribute to the production of L-kynurenine following indoleamine 2,3-dioxygenase induction and immune activation. Quinolinic acid may be directly synthesized from L-tryptophan in both macrophages and certain types of liver cells, although uptake of quinolinic acid precursors from blood may contribute to quinolinic acid synthesis in cells that cannot convert L-kynurenine into quinolinic acid.
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PMID:4-Chloro-3-hydroxyanthranilate, 6-chlorotryptophan and norharmane attenuate quinolinic acid formation by interferon-gamma-stimulated monocytes (THP-1 cells). 847 Oct 29


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