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)

We have previously reported that invasiveness of mouse glioma G-26, which expresses CD44 adhesion molecule, was inhibited in vitro following treatment with anti-CD44 antibody or mouse interferon alpha/beta (MuIFN alpha/beta). Here, we evaluated whether the expression of transmembrane CD44 adhesion molecule and/or secretion of extracellular matrix metalloproteinases (MMPs) were affected when glioma cell invasion was inhibited. Flow cytometric evaluation of CD44 adhesion molecule expression in G-26 glioma using anti-CD44 antibody, confirmed that G-26 cells were CD44+. Following 3-day treatment with MuIFN alpha/beta at 8 x 10(2) or 8 x 10(3) IU/ml of glioma cells, the expression of CD44 was not significantly affected as reflected by CD44+ cell number and fluorescence intensity. The pretreatment of glioma cells for 1 day with anti-CD44 antibody resulted in a 30-60% decrease of CD44 expression. This coincided with significantly (p < 0.05) lower cell activity as judged by MTT assay for mitochondrial activity. The zymographic evaluation of MMP activity in the G-26 glioma cell culture showed a high level of the active form of MMP-2. This level of MMP-2 was decreased following 3 day treatment of G-26 glioma cells with either 8 x 10(2) or 8 x 10(3) IU/ml of MuIFN alpha/beta but only the latter concentration produced statistically significant 55% decrease. However, following a 1 day treatment of G-26 glioma cells with anti-CD44 antibody, the level of active MMP-2 form was not significantly affected. These findings indicate that while the inhibitory effect of IFN on glioma invasion was accompanied by a decreased level of the active form of MMP-2 released extracellularly, the expression of the transmembrane CD44 adhesion molecule was not affected. Conversely, anti-CD44 antibody pretreatment of G-26 glioma, which led to the inhibition of glioma invasion, resulted in decreased CD44 expression and lower cell activity but had no effect on the MMP-2.
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PMID:CD44 expression and MMP-2 secretion by mouse glioma cells: effect of interferon and anti-CD44 antibody. 1120 62

Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.
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PMID:Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma. 1130 15

Since malignant glioma displays moderate resistance to conventional therapy, a new treatment modality is needed to improve the outcome of patients with these tumors. In this study, we examined whether combination stimulation with interferon alpha (IFN-alpha) and retinoic acid (RA) affected proliferation of the glioblastoma cell line GB 12 in vitro. Stimulation with IFN-alpha alone inhibited the GB 12 cell proliferation in a dose/time-dependent fashion, as assessed by WST-1 assay and uptake of 3H-thymidine, while RA limited it only slightly. The anti-proliferative action of IFN-alpha against glioblastoma cells was enhanced by the addition of RA. The IFN-alpha/RA combination also induced apoptosis in a substantial portion of the cells, compared with either reagent alone. Bcl-2 family proteins, regulating apoptosis, were altered by these stimuli: Bcl-2 was down-regulated, while Bax-alpha was up-regulated, especially by the combination. These findings suggest that the IFN-alpha/RA combination would synergistically affect glioblastoma cell growth, probably through apoptosis induction as well as a decreased cellular DNA synthesis.
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PMID:Combined stimulation with interferon alpha and retinoic acid synergistically inhibits proliferation of the glioblastoma cell line GB12. 1239 8

Tissue factor pathway inhibitor-2 (TFPI-2), a serine protease inhibitor abundant in the extracellular matrix, is expressed in high amounts in low-grade, non-invasive glioma cells but in low amounts in high-grade, highly invasive glioma cells. Overexpression of TFPI-2 by highly invasive glioma cells reduces their invasiveness and thus may be useful in cancer therapy. The mechanisms underlying the transcriptional regulation of TFPI-2 are not well elucidated. We previously reported that the -312 to +1 region of TFPI-2 was critical for the minimal, inducible regulation of TFPI-2 in gliomas. This region harbors sites for several transcription factors, including SP1 (-192 to -183 and -135 to -128), AP-1 (-310 to -300, -213 to -204, and -163 to -154), NF-kappaB (-229 to -221), an NF-kappaB-like site (-291 to -281), and Lyf-1 (-260 to -252). Here we transiently transfected low-grade Hs683 glioma cells with mutant constructs to clarify the role of these transcription factors in TFPI-2 regulation. Addition of phorbol 12-myristate 13-acetate, 1,2-diacyl-sn-glycerol, IFN-gamma, or IFN-alpha induced the expression of TFPI-2 wild-type promoter construct as well as TFPI-2 protein and mRNA in Hs683 cells. Mutations at either of two AP-1 sites (-310 to -300 and -163 to -154) or either of two SP1 sites (-192 to -183 and -135 to -128) resulted in reduced TFPI-2 activity, regardless of the presence of stimulator compounds, and reduction in DNA-protein binding (by electrophoretic mobility shift assay).
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PMID:Physiological and chemical inducers of tissue factor pathway inhibitor-2 in human glioma cells. 1273 94

Our clinical studies revealed significantly increased soluble HLA-G (sHLA-G) plasma levels in patients suffering from malignant melanoma, glioma, breast and ovarian cancer. Specific ELISpot assays demonstrate that sHLA-G molecules expressing intron-4 sequences are preferentially secreted by peripheral blood monocytes. In vitro, the sHLA-G secretion of monocytes and tumor cells was strongly enhanced by TH1 cytokines like IFN-alpha, -beta, -gamma whereas TH2 cytokines (e.g. IL-4, -10) had minor effects. As sHLA-G can inhibit the functions of T and NK cells high concentration of these molecules should systemically or at the tumor side reduce the immune surveillance and thus favour the progression of cancer.
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PMID:Secretion of sHLA-G molecules in malignancies. 1470 17

The pathology of Parkinson's disease involves oxidative damage to dopaminergic neurons of the substantia nigra. Oxidation of the dopamine (DA) neurotransmitter itself may contribute to the generation of a reactive oxygen species (ROS) and subsequent neurodegeneration. Glia cells can either exacerbate injury or exert protective properties on local neurons in the brain. We investigate glial antioxidant enzyme systems relative to ROS generated during cytokine activation, monoamine oxidase (MAO) activity and autoxidation of DA in glioma cells. Rat C6 glioma cells stimulated with lipopolysaccharide Escherichia coli 0111:B4 and interferon gamma (LPS/IFN-g) produced high levels of nitric oxide (241 nmol mg(-1) protein 24 h(-1)) but not superoxide (O(-) (2)) or hydrogen peroxide (H(2)O(2)). Basal C6 cells exhibited a rapid and robust capacity to remove exogenous H(2)O(2) within minutes. Preincubation with sodium azide but not buthionine-[S, R]-sulfoximine attenuated this response, indicating catalase as the primary enzyme responsible for this effect. The glioma catalase reaction rate was slightly attenuated by exposure to LPS/IFN-g for 24 h. However, the reduction in catalase activity was not due to nitric oxide, because both the supernatant and sodium nitroprusside had no effect on isolated catalase enzyme activity. Hydrogen peroxide was produced only through substrate-driven MAO activity in prepared lysate. However, the quantity of H(2)O(2) produced per unit time (0.46 nmol mg(-1) protein min(-1)) was negligible compared with the enormous capacity for its removal by catalase (213.9 nmol mg(-1) protein min(-1)) (> or =462 x greater). Similarly, H(2)O(2) generated by DA autoxidation per unit time (0.28 nmol mg(-1) protein equiv. min(-1)), was rapidly dissolved by glioma cells at high capacity (> or =750 x greater). In conclusion, C6 cells produce nitric oxide under cytokine/endotoxin-stimulated conditions. Moreover, C6 cells exhibit a dynamic H(2)O(2) scavenging capacity, with ample facility to dispose of the peroxide generated by both MAO activity and spontaneous DA autoxidation.
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PMID:Glioma cell antioxidant capacity relative to reactive oxygen species produced by dopamine. 1505 4

Halofuginone, a widely used alkaloid coccidiostat, is a potent inhibitor of collagen alpha 1 (I) and matrix metalloproteinase 2 gene expression. Halofuginone also suppresses extracellular matrix deposition and fibroblast proliferation. It was recently shown to be effective in suppression of bladder carcinoma and glioma. This study sought to evaluate the effect of treatment with halofuginone on growth of hepatocellular carcinoma (HCC) in mice. Athymic Balb/c mice were injected subcutaneously with 10(7) human hepatoma cells (Hep3B), followed by treatment with halofuginone administered in the diet (750 microg/kg) starting on day 3, before tumour innoculation. The control group was received a normal diet. Mice were followed for survival, tumour volume and serum alpha-fetoprotein (alpha FP). The mechanism of the anti-tumour effect of halofuginone was determined in vitro by assessing tumour cell growth, and by measuring the serum concentrations of interferon-gamma (IFN gamma) and interleukin 2 (IL2). Halofuginone treatment induced almost complete tumour suppression in treated mice. Mortality rates were 10% and 50%, in halofuginone-treated and control mice, respectively (P<0.001). No visible tumour was observed in treated mice, as compared with a 364 mm3 tumour in control mice. Serum alpha FP were 0.1 and 212 ng/ml in treated and control mice, respectively (P<0.005). Halofuginone significantly inhibited HCC proliferation in vitro. Maximal inhibition of 64% of tumour cell growth was observed at a concentration of 10(-8) M. The anti-tumour effect was mediated via a significant increase in IFN gamma and IL2 (90 vs. 35, and 210 vs. 34 pg/ml in treated and control groups, respectively, P<0.005). Treatment with halofuginone effectively suppressed the progression of HCC in mice. This effect may be associated with a direct anti-tumour effect, and/or enhancement of a systemic immune response.
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PMID:Suppression of hepatocellular carcinoma growth in mice by the alkaloid coccidiostat halofuginone. 1517 99

We tested whether modulation of the CNS-tumor microenvironment by delivery of IFN-alpha-transduced dendritic cells (DCs: DC-IFN-alpha) would enhance the therapeutic efficacy of peripheral vaccinations with cytokine-gene transduced tumor cells. Mice bearing intracranial GL261 glioma or MCA205 sarcoma received peripheral immunizations with corresponding irradiated tumor cells engineered to express IL-4 or GM-CSFs, respectively, as well as intratumoral delivery of DC-IFN-alpha. This regimen prolonged survival of the animals and induced tumor-specific CTLs that expressed TRAIL, which in concert with perforin and Fas ligand (FasL) was involved in the tumor-specific CTL activity of these cells. The in vivo antitumor activity associated with this approach was abrogated by administration of neutralizing mAbs against TRAIL or FasL and was not observed in perforin-/-, IFN-gamma-/-, or FasL-/- mice. Transduction of the tumor cells with antiapoptotic protein cellular FLIP rendered the gene-modified cells resistant to TRAIL- or FasL-mediated apoptosis and to CTL killing activity in vitro. Furthermore, the combination therapeutic regimen was ineffective in an intracranial cellular FLIP-transduced MCA205 brain tumor model. These results suggest that the combination of intratumoral delivery of DC-IFN-alpha and peripheral immunization with cytokine-gene transduced tumor cells may be an effective therapy for brain tumors that are sensitive to apoptotic signaling pathways.
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PMID:Delivery of dendritic cells engineered to secrete IFN-alpha into central nervous system tumors enhances the efficacy of peripheral tumor cell vaccines: dependence on apoptotic pathways. 1608 51

The influence of environmental pH on the production of tumoricidal free radical nitric oxide (NO) was investigated in mouse fibrosarcoma L929 and rat glioma C6 cell lines. A combination of IFN-gamma and IL-1 induced a significant NO release and subsequent reduction of cell viability in tumor cell lines. Acidification of cell culture medium reduced tumor cell NO production in a pH-dependent manner. While the inhibitory effect of acidosis on NO production in C6 cells was associated with a further decrease in cell viability, it completely rescued L929 cells from NO-dependent apoptotic and necrotic death. Acidic pH diminished IFN-gamma+ IL-1-induced expression of inducible NO synthase (iNOS) mRNA and protein, and abolished the activation of iNOS transcription factor IRF-1 in L929 cells. Moreover, extracellular acidosis significantly impaired cytokine-induced phosphorylation of MAP kinase p44/42 (ERK1/2) and subsequent expression of transcription factor c-Fos in L929 cells. Finally, mild acidosis (pH 6.8) augmented, while severe acidosis (pH 6.0) reduced, IFN-gamma-induced iNOS activation/NO release and NO-dependent anticancer activity of rat and mouse macrophages. Taken together, our findings indicate that modulation of macrophage and tumor cell iNOS by an acidic microenvironment might influence the progression of NO-sensitive solid tumors.
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PMID:Acidosis affects tumor cell survival through modulation of nitric oxide release. 1641 2

Induction of proinflammatory cytokines in response to malignant cells is an integral component of immune response to control tumor development. However, recent evidences have suggested that tumor cells may evade the immune system and exploit inflammatory responses to enhance its own growth. An exemplary example is the highly invasive and tumor necrosis factor (TNF)alpha-resistant glioblastoma, whose growth is associated with TNFalpha expression. We thus examined whether the tumor takes advantage of TNFalpha overexpression to enhance its invasiveness. To delineate the contribution of inflammation in tumor migration, we demonstrated that the role of proinflammatory cytokines on matrix metalloproteinases-3 (MMP-3) expression, and its consequent effects on the invasiveness of a human glioma cell-line, T98G. By using Matrigel Invasion Chamber, T98G cell migration was significantly enhanced in response to TNFalpha. In contrast, interferon-gamma (IFN gamma) reduced both basal and TNFalpha-enhanced cell invasion. To investigate the mechanisms involved, we demonstrated that TNFalpha upregulated mRNA and protein expression of MMP-3 in T98G cells, whereas IFN gamma downregulated the MMP-3 expression. The role of MMP-3 in glioma invasiveness was further confirmed by transfecting MMP-3 siRNA in T98G to abrogate the TNFalpha-enhanced cell invasion. To delineate the mechanisms further, we showed that IFN gamma exerts an inhibitory effect on the binding of TNFalpha-activated Ets-1 and NF kappa B to their respective enhancer elements found in MMP-3 promoter. In summary, our results indicated that TNFalpha enhances the invasiveness of T98G glioma cells through MMP-3 induction, and such enhancement of cell migration can be inhibited by IFN gamma.
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PMID:Interferon-gamma regulation of TNFalpha-induced matrix metalloproteinase 3 expression and migration of human glioma T98G cells. 1752 Jun 72


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