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)

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

Transforming growth factor beta-2 (TGF-B2) is secreted by glioma cells and is known to decrease leukocyte-endothelium interaction. TGF-B2 alone and in conjunction with soluble tumor necrosis factor (TNF) p55 receptor, was found to decrease the expression of TNF induced VCAM-1 on the malignant glioma cell line A-172 and human cerebral microvessel endothelial (CNS-EC) cells. Co-culture of A-172 glioma cells led to a decrease in VCAM-1 expression; this effect on CNS-EC in co-culture could be simulated by glioma supernatant alone. These results suggest that malignant gliomas, by secreting TGF-B2 and releasing soluble TNF receptors, modulate adhesion molecules.
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PMID:TGF-B2 and soluble p55 TNFR modulate VCAM-1 expression in glioma cells and brain derived endothelial cells. 905 71

Exposure to lipopolysaccharide (LPS) combined with phorbol-12-myristate-13-acetate (PMA) stimulates de novo synthesis of inducible nitric oxide synthase (NOS-2) in C6 glioma cells. Ethanol dose-dependently inhibits C6 cell NOS-2 activity, as measured by nitrite accumulation in culture medium, when present during LPS plus PMA treatment. The present study reports on mechanisms related to this inhibition. Ethanol added directly to cytosolic extracts did not inhibit NOS-2 catalytic activity, nor did ethanol decrease nitrite accumulation when added to cultures 24 hr after LPS plus PMA treatment. In contrast, NOS-2 enzymatic activity was significantly decreased in cytosolic extracts from cultures simultaneously exposed to ethanol and LPS plus PMA for 24 hr. Immunoblot analysis showed a coincident decrease in NOS-2 protein immunoreactivity. RNA analysis revealed that NOS-2 mRNA was decreased at both 12 and 24 hr during LPS plus PMA induction in the presence of ethanol. Subsequent experiments confirmed that 12-hr exposure to ethanol was sufficient to inhibit LPS/PMA-induced NOS-2 activity. Ethanol exposure also inhibited NOS-2 activity induced by LPS plus interferon-gamma, by LPS plus tumor necrosis factor-alpha and by tumor necrosis factor-alpha alone. These data point to an inhibitory ethanol effect at a site downstream from cytokine receptor activation and second messenger signal transduction mechanisms leading to suppression of NOS-2 gene expression in C6 cells.
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PMID:Suppression by ethanol of inducible nitric oxide synthase expression in C6 glioma cells. 910 44

Malignant glioma cells are susceptible to CD95(Fas/APO-)-mediated apoptosis triggered by agonistic antibody. Here we examined the proapoptotic effects of the natural CD95 ligand, a cytotoxic cytokine homologous to tumor necrosis factor, on malignant glioma cell lines LN-229, LN-308 and T98G. We assessed whether glioma cell killing is synergistically enhanced by cotreatment with CD95 ligand and chemotherapeutic agents, including doxorubicin, carmustine, vincristine, etoposide, teniposide, 5-fluorouracil and cytarabine. Synergy was examined at low concentrations of cytotoxic drugs and CD95 ligand with a defined effect level (IC15). Short-term-cytotoxicity assays showed prominent killing of the glioma cells by CD95 ligand but not by the drugs at relevant concentrations. CD95 ligand induced apoptosis in the acute toxicity paradigm was augmented by doxorubicin and vincristine. Growth-inhibition assays revealed prominent synergy between CD95 ligand and all drugs examined. The best synergy was obtained with CD95 ligand and doxorubicin, vincristine or teniposide. The strong synergistic antiproliferative effects were observed at much lower concentrations of CD95 ligand and cytotoxic drugs than the moderate synergistic acute cytotoxic effects. All cell lines examined express the Bcl-2 protein. LN-229 has partial wild-type p53 activity. T98G has mutant p53, LN-308 has a deleted p53 gene and lacks p53 protein expression. Thus, synergistic effects of CD95 ligand and cytotoxic drugs were observed in cell lines exhibiting two features thought to play a role in the chemoresistance of human malignant glioma cells: loss of wild-type p53 activity and acquisition of bcl-2 expression. Ectopic expression of murine bcl-2 conferred partial protection from CD95 ligand and drugs when administered alone but did not interfere with the mechanisms underlying the synergistic effects of CD95 ligand and chemotherapeutic drugs.
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PMID:Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. 911 85

The regulation of adhesion molecule expression in malignant gliomas by tumor necrosis factor-alpha (TNF) and soluble TNF receptors (TNFR) was examined in the malignant glioma cell line A-172 and in 2 primary glioblastoma cell cultures (LA-492 and LA-567). A-172 cells expressed only the p55 TNF receptor transcripts and protein. The 2 primary cell cultures expressed both the p55 and p75 TNF receptors. In A-172 cells and in 1 of 2 primary glioma cell cultures, TNF upregulated the expression of ICAM-1 and VCAM-1, A-172 and both primary glioma cultures also shed their TNF receptors in the absence of activation by stimulating agents. Soluble p55 (sp55) receptors, but not soluble p75 (sp75) receptors, were found to reduce the TNF induced VCAM-1 and ICAM-1 expression in both the glioma cell line and the primary cell culture. Immunostaining of malignant glioma sections confirmed the presence of soluble TNFR and adhesion molecule expression in glioma cells in situ. These data suggest that soluble TNF receptors may play a role in the mechanism by which malignant gliomas downregulate the effects of infiltrating immune-competent cells.
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PMID:Soluble TNF-alpha receptors are constitutively shed and downregulate adhesion molecule expression in malignant gliomas. 914 67

Expression of tenascin, an extracellular matrix glycoprotein, was measured in glioma cell lines using a newly established enzyme immunoassay. Secreted tenascin was found at concentrations greater than 800 ng/ml in eight of 14 glioma, three small cell lung carcinoma, two melanoma, and one sarcoma cell lines. The remaining six glioma and other carcinoma cell lines, and cell lines originating from normal tissues demonstrated low levels or no secretion into the supernatant. The glioma cell line, U-251-MG nu/nu, which has almost 100% transplantability in nude mice, had the highest expression level of tenascin among the glioma cell lines examined. Even low secretor glioma cell lines released high concentrations of tenascin, detectable by assaying the NP-40 solubilized cell lysates. Flow cytometric analysis revealed that tenascin was located on both the cell surface and primarily in the cytoplasm of glioma cells. When the glioma cell lines were exposed to tumor necrosis factor-alpha (TNF-alpha), levels of secreted tenascin increased between 36% and 380%, whereas transforming growth factor-beta induced only minimal changes. These results suggest that glioma cell lines may be classified according to the degree of tenascin secretion/expression: high secretor type, low secretor type, and non-expressing type. The increase in tenascin secretion by TNF-alpha suggests that the expression of tenascin in glioma growth and development may be mediated through a cytokine network.
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PMID:Enzyme immunoassay of glioma cell tenascin secretion and augmentation by tumor necrosis factor-alpha. 918 37

Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. The aim of this study was to determine if low doses of tumor necrosis factor-alpha (TNF-alpha) could augment the effects of radiation in a glioma xenograft model and to evaluate hematological and other parameters that might indicate treatment-related toxicity. Nude mice were injected subcutaneously with C6 rat glioma cells and randomized into groups. Two different time-dose protocols were employed using intravenous human recombinant TNF-alpha and radiation beginning within 24 h after tumor cell implantation. The administration of radiation as a single agent slowed tumor progression, whereas TNF-alpha alone had no effect. However, TNF-alpha, especially when given twice per week before radiation for a total of four doses each, significantly increased the efficacy of the radiation. Low leukocyte counts were associated with combination treatment, whereas transforming growth factor-beta 1 levels were depressed in all treated groups. TNF-alpha did not modulate radiation-induced inhibition of C6 cell proliferation in vitro. The data show that TNF-alpha at relatively nontoxic doses can significantly enhance the antitumor effects of radiation against a rapidly growing glioma. This effect was more than additive, because TNF-alpha alone did not slow tumor progression.
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PMID:Tumor necrosis factor-alpha enhances antitumor effects of radiation against glioma xenografts. 930 29

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) occurs in CNS tissue in neurological disorders, infection, and injury. Its excessive production is believed to contribute to local pathology, in which case modulation of TNF-alpha production should promote survival of neural tissue. The neuropeptide alpha-melanocyte stimulating hormone [alpha-MSH (1-13)] inhibits TNF-alpha production in vivo and in vitro, and in this research we tested the capacity of the peptide, and of an anti-inflammatory COOH-terminal tripeptide fragment of it, to inhibit TNF-alpha production induced by bacterial endotoxin in cells of a human glioma line (A-172, anaplastic astrocytoma cells). Both peptides were effective, although the alpha-MSH (1-13) sequence was more potent. Preincubation of the cells with alpha-MSH (1-13) markedly increased its effectiveness. The anticytokine effect of alpha-MSH in glioma cells may be mediated by human melanocortin-1 receptors; mRNA for this receptor subtype was isolated from resting A-172 cells. These results, combined with prior evidence of effectiveness of alpha-MSH molecules in modulating inflammatory processes and of their low toxicity, suggest that the molecules may be useful in the treatment of CNS disorders that have an inflammatory component.
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PMID:A potential mechanism of local anti-inflammatory action of alpha-melanocyte-stimulating hormone within the brain: modulation of tumor necrosis factor-alpha production by human astrocytic cells. 932 43

Hypericin and tamoxifen are experimental agents for the adjuvant chemotherapy of malignant glioma. We report that hypericin and tamoxifen induce apoptosis of 7 human malignant glioma cell lines in a concentration- and time-dependent manner. Illumination is essential for the cytotoxicity of hypericin but not tamoxifen. Apoptosis is unaffected by inhibitors of RNA and protein synthesis or free radical scavengers, does not require wild-type p53 activity, and occurs in glioma cells expressing high levels of bcl-2. There is no correlation between hypericin and tamoxifen-induced cytotoxicity and inhibition of protein kinase C (PKC). Ectopic expression of a murine bcl-2 transgene provides modest protection from tamoxifen but does not affect hypericin toxicity. Hypericin and tamoxifen do not modulate glioma cell killing induced by tumor necrosis factor-alpha (TNF-alpha) or CD95 ligand. Both drugs augment the acute cytotoxicity of various cancer chemotherapy drugs but fail to shift their EC50 values in modified colony formation assays. These data do not provide further supportive evidence how to enhance the limited efficacy of tamoxifen treatment for human malignant glioma. However, hypericin is a promising agent for the treatment of malignant glioma if local photodynamic activation of hypericin in the glioma tissue can be achieved.
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PMID:Hypericin-induced apoptosis of human malignant glioma cells is light-dependent, independent of bcl-2 expression, and does not require wild-type p53. 932 22

The effect of intracarotid infusion of the bradykinin analog, RMP-7, on blood-to-tumor and blood-to-brain transport of three cytokines were investigated. Wistar rats with RG2 gliomas were utilized and a unidirectional transfer constant, Ki, was determined using quantitative autoradiography. Interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-2 (IL-2) were labeled with 125Iodine for quantitative transport studies using autoradiography. Radiolabeled cytokines were injected as an intravenous bolus. Intracarotid infusion of RMP-7 (0.1 microgram kg-1 min-1) increased the selective transport to tumors of IFN-gamma by 3.97-fold (p < 0.005), of TNF-alpha by 5.30-fold (p < 0.005), and of IL-2 by 4.34-fold (p < 0.005), compared to intracarotid saline infusion. To determine whether the increased IFN-gamma or TNF-alpha transport to tumors with RMP-7 could enhance expression of intercellular adhesion molecule 1 (ICAM-1) in tumors, ICAM-1 expression in RG2 glioma was evaluated by immunohistochemistry. Both IFN-gamma and TNF-alpha increased ICAM-1 expression of RG2 cells in vitro. In vivo, intracarotid infusion of IFN-gamma combined with RMP-7 significantly enhanced ICAM-1 expression in intracerebral RG2 gliomas compared to infusion of IFN-gamma without RMP-7. Expression of ICAM-1 was not enhanced by TNF-alpha combined with RMP-7. Intracarotid infusion of RMP-7 is a novel method of cytokines delivery to brain tumors.
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PMID:Enhanced cytokines delivery and intercellular adhesion molecule 1 (ICAM-1) expression in glioma by intracarotid infusion of bradykinin analog, RMP-7. 932 27


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