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)

Most tumors, including gliomas, are resistant to tumor necrosis factor (TNF) cytotoxicity unless protein or RNA synthesis is inhibited. We investigated the effects of the combined use of TNF-alpha and cisplatin (CDDP) on cultured malignant glioma cells, T98G, U373MG, A172, and U87MG. All glioma cell lines were sensitive to treatment with CDDP but resistant to TNF-alpha during 24 h-incubation. The combined use of CDDP and TNF-alpha had synergistic effects on T98G and U87MG but not on U373MG and A172 cells. Sequential treatments showed that only pretreatment with CDDP for 2 h followed by TNF-alpha for 22 h was synergistic on cell cytotoxicity. Annexin V-flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling assay showed that TNF-alpha can induce apoptosis in cells treated with CDDP. Although only sensitive cell lines express transcripts for p75 TNF receptor 2, changes in TNF receptors were not found to contribute to the susceptibility to TNF-alpha. The production of interleukin-6, a representative cytoprotective cytokine, from glioma cells stimulated by TNF-alpha was suppressed by the combined use of actinomycin D, but not CDDP. Our results indicate that CDDP can sensitize glioma cells to TNF-alpha-induced apoptosis by a mechanism other than blocking the cytoprotective protein production.
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PMID:Sensitization of human malignant glioma cell lines to tumor necrosis factor-induced apoptosis by cisplatin. 1145 Dec

Thrombin (THR) plays a key role in the brain under physiological and pathological conditions. Several of the biological activities of thrombin have been shown to be mainly driven through activation of protease-activated receptor-1 (PAR-1)-type thrombin receptor. Here we have studied the effect of THR and PAR-1-activating peptide (PAR1-AP), SFLLRN, on cytokine-induced expression of inducible nitric oxide (iNOS), a prominent marker of astroglial activation using the rat C6 glioma cells. In this cell line, THR (1-10 U/mL) and PAR1-AP (1-100 microM) induced a significant concentration-dependent increase both of IFN-gamma- (250 U/mL) or TNF-alpha- (500 U/mL) induced NO release. The observed increase of NO production was related to an enhancement of iNOS expression as measured in cell lysates prepared from different treatments by using SDS-PAGE followed by western blot analysis. The effect of THR, but not that of PAR1-AP, was significantly inhibited by hirulog(TM) (60 microg/mL), a specific and stochiometric THR inhibitor or by cathepsin-G (40 mU/mL), an inhibitor of PAR-1. In conclusion our data suggest a role for THR through activation of PAR-1 in the induction of astroglial iNOS, and further support the hypothesis that THR may function as an important pathophysiological modulator of the inflammatory response.
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PMID:Thrombin and PAR-1 activating peptide increase iNOS expression in cytokine-stimulated C6 glioma cells. 1170 59

Immunotherapies, although promising in preclinical studies, have not yet enhanced the survival of patients with glioblastomas. To further understand the immunobiology of glioblastomas in clinical settings, we examined 53 cytokine or cytokine receptor transcripts in 12 human glioblastomas and 6 human glioblastoma cell lines and correlated the findings with the degree of inflammation. Multi-probe RNase protection assays were used to examine Th1, Th2, and Th3 cytokine and cytokine receptor expression. Th2 [interleukin (IL)-6, leukemia inhibitory factor and oncostatin M] and Th3 (transforming growth factor-beta1, 2, 3) cytokine and their receptor transcripts were strongly expressed in almost all glioblastomas and glioma cell lines. Two other Th2 cytokine receptor subunit transcripts (IL-4Ralpha and IL-13Ralpha) were also commonly detected. In contrast, although Th1 cytokine receptors tumor necrosis factor (TNF) RI, interferon (IFN)-gammaRalpha, IFN-gammaRbeta, were detected, their cytokines (IFN-gamma, TNF-alpha, lymphotoxin-alpha) were not. Transcripts for IL-2 family cytokine (IL-2, IL-7, IL-9, IL-15) and receptors (IL-2Ralpha, IL-2Rbeta, gammac, IL-7Ralpha, IL-9Ralpha, IL15Ralpha) and IL-12 family cytokine (IL-12p40) and receptors (IL-12Rbeta1 and IL-12beta2) were essentially absent in both tumors and cell lines. Immunohistochemical methods showed sparse T lymphocyte infiltrates and numerous microglia in the glioblastomas. This pattern indicates an 'immunosuppressive status' in glioblastomas and could account for the failure of immunotherapy in such tumors.
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PMID:Cytokine and cytokine receptor mRNA expression in human glioblastomas: evidence of Th1, Th2 and Th3 cytokine dysregulation. 1181 Jan 84

The combined therapeutic effect of cytokine-producing cancer cell vaccines and local radiotherapy was studied in a mouse glioma 261 (GI261) brain tumor model. Brain tumor-bearing mice were treated with cytokine (IL -4, IL-6, IL-7, GM-CSF, TNF-alpha, LIF, LT) producing vaccines made by in vitro transduction of GI261 cells with the corresponding adenoviral vectors. Vaccines producing either IL-4 or GM-CSF cured 20-40% of mice. The antitumor effect strongly depended on the secreted cytokine level. Vaccination therapy induced specific activation of cytotoxic T lymphocytes measured by cell-mediated cytotoxicity assay. Brain tumors were heavily infiltrated by CD4+ lymphocytes after treatment with IL-4- or GM-CSF-secreting cells. GM-CSF vaccination induced moderate CD8+ infiltration, as well. Depleting either CD4+ or CD8+ lymphocyte subsets abolished the anticancer effect of GM-CSF-expressing cells. Strong synergism was observed by combining cytokine vaccination (GM-CSF, IL-4, IL-12) with local tumor irradiation: about 80-100% of the glioma-bearing mice was cured. The high efficiency of combined treatment was maintained even under suboptimal conditions when neither of the modalities cured any of the mice alone. This suggests that vaccination therapy might open a new potential in the clinical treatment of high-grade gliomas when applied as adjuvant to existing treatment modalities.
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PMID:Local tumor irradiation augments the antitumor effect of cytokine-producing autologous cancer cell vaccines in a murine glioma model. 1191 44

Gliomas are among the most resistant tumors to conventional anti-tumor therapy, and are typified by their highly infiltrative nature and ill-defined borders. Macrophages constitute a major proportion of the tumor cell mass in both primary human gliomas and as shown here, a CNS-1 glioma model. The objective of this study was to identify tumor-cell-derived chemotactic factor(s) which participate in macrophage recruitment into tumors in vivo. This study demonstrates the constitutive expression of monocyte chemoattractant protein-1 (MCP-1), a potent monocyte chemoattractant, by the rat astrocytoma cell line CNS-1. Characterization of cytokine expression by CNS-1 cells in vitro revealed the constitutive expression of TGF-beta but not other proinflammatory cytokines. However, numerous cytokines were detected in CNS-I tumors in vivo including Ltbeta, IL-1alpha, IL-1beta, TNF-alpha, TNF-beta, IL-10, and IFN-gamma. Attenuation of MCP- I release from CNS-1 cells using an anti-sense approach revealed no significant alterations in macrophage infiltration into tumors in vivo, suggesting redundancy in the signal(s) involved in macrophage recruitment. Depletion of peripheral macrophages using liposome-encapsulated clodronate revealed no significant differences in tumor growth or in the degree of macrophage infiltration into CNS-1 tumors in vivo. These results indicate that CNS-1 cells produce chemotactic factors which likely participate in macrophage recruitment into tumors in vivo. Whether or not macrophage recruitment confers a growth advantage for the tumor remains to be determined.
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PMID:MCP-1 expression in CNS-1 astrocytoma cells: implications for macrophage infiltration into tumors in vivo. 1194 21

Globoid cell leukodystrophy (Krabbe disease) is characterized by the accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is a substrate for the deficient enzyme (galactocerebroside beta-galactosidase). This study underscores the possible role of psychosine in the effect of inducible nitric oxide synthase (iNOS) -derived NO in the pathophysiology of this demyelinating disease. For the first time, we provide evidence of the expression of iNOS in CNS of Krabbe patient and show that the iNOS-expressing cells in the CNS were astrocytes. Psychosine potentiated the LPS-induced production of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) in primary rat astrocytes and regulated the cytokine-mediated production of NO in C6 glioma and primary rat astrocyte. Psychosine induced cytokine-mediated nuclear translocation of AP-1 and C/EBP by potentiating the expression of Fra-1 and C/EBP-delta proteins. This suggests that psychosine maintained or sustained the cytokine-primed expression of iNOS by further potentiating the nuclear translocation of AP-1 and C/EBP without modulating the cytokine-mediated transcription activity of NF-kappaB. This study hypothesizes that accumulated psychosine leads to production of cytokines and iNOS expression. The ensuing excessive production of NO and ONOO- may play a role in pathogenesis of Krabbe disease.
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PMID:Galactosylsphingosine (psychosine)-induced expression of cytokine-mediated inducible nitric oxide synthases via AP-1 and C/EBP: implications for Krabbe disease. 1197 30

The major goal of this study was to evaluate the safety and efficacy of TNF-alpha gene therapy (pGL1-TNF-alpha) in combination with proton radiation in an orthotopic brain tumor model. C6 glioma cells were implanted into the left hemibrain of athymic rats (day 0). On day 5, pGL1-TNF-alpha (19 microg/10 microl) was injected into the same site; appropriate control groups were included. Proton irradiation (10 Gy, single fraction) was performed 18-20 h thereafter and, on day 10, a portion of animals from each group was assayed. Nearly all tumor-bearing groups had lower body mass compared to those without tumor; brain mass was somewhat increased with plasmid (pGL1-TNF-alpha or pWS4) injection (p<0.05). Histopathological analysis of brain sections revealed that rats receiving pGL1-TNF-alpha/proton irradiation had the smallest tumors and lowest number of mitotic tumor cells, although survival time for animals kept long-term was not significantly prolonged. A decline in leukocyte populations was noted with combination treatment compared to controls (p<0.05), but no differences were found compared to groups receiving each modality alone. Based on DNA synthesis, the pGL1-TNF-alpha/proton irradiated group had the highest levels of leukocyte activation. The highest percentage of lymphocytes expressing the CD71 activation marker occurred with pGL1-TNF-alpha, whereas the proton-irradiated group had the highest percentage of activated NK cells (NK1.1+/CD71+). No significant differences were found in erythrocyte and thrombocyte numbers, hemoglobin, and hematocrit. Overall, the data indicate that pGL1-TNF-alpha/proton treatment results in a measurable antitumor effect and is safe under the conditions used.
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PMID:TNF-alpha gene and proton radiotherapy in an orthotopic brain tumor model. 1211 18

Cell membrane dielectric properties of five different cultivated cell lines and human peripheral blood mononuclear cells (PBMC) were determined from dielectrophoretic crossover frequency measurements on a 5 x 5 microelectronic chip array. Based on distinct dielectric property differences between individual cell types, efficient cell separations were achieved by dielectrophoresis on this 5 x 5 array, which included separation of monocytic cells (U937) or human T cell leukemia virus type 1 (HTLV-1) tax-transformed cells (Ind-2) from PBMC, as well as separation of neuroblastoma cells (SH-SY5Y) from glioma cells (HTB). The purity of dielectrophoretically separated cells can be greater than 95%. Expression profiles of IL-1, TNF-alpha, and TGF-beta genes for U937 cells mixed with PBMC before and after the separation were determined by a means of electric field-facilitated hybridization on a 10 x 10 microelectronic chip array. By using the expression levels of pure U937 cells as a control, it was shown that the gene expression profiles of the postseparation cells were significantly different from those of the preseparation cell mixtures. The increase in gene expression levels for U937 cells upon lipopolysaccharide induction could be accurately determined only in the postseparation cells, while the preseparation samples masked these changes. Furthermore, by cultivating the separated HTB and SH-SY5Y cells and measuring expression of the stress-related gene c-fos, dielectrophoretic forces were shown to have little effect on cell survival and stress. The presented approach of using microelectronic chip arrays for both cell separation and gene expression profiling provides a great potential for accurate genetic analysis of specific cell subpopulations in heterogeneous samples.
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PMID:Dielectrophoretic cell separation and gene expression profiling on microelectronic chip arrays. 1213 41

The involvement of phosphatidylinositol 3 (PI 3)-kinase in the signalling pathways leading to MMP-9 expression in glioma cells remains unclear. Here, we report that PI 3-kinase inhibits MMP-9 expression induced by either IL-1 or TNF-alpha in rat C6 glioma cells. Using zymography and semi-quantitative RT-PCR analysis, we showed that treatment of C6 cells with wortmannin, an inhibitor of PI 3-kinase activity, potentiated the expression of MMP-9 induced by both cytokines. In contrast, platelet-derived growth factor (PDGF), an inducer of PI 3-kinase activity in C6 cells, inhibited IL-1- or TNF-alpha-induced MMP-9 secretion. Accordingly, this inhibition by PDGF was prevented by wortmannin. Furthermore, stable C6 clones over-expressing the dominant-negative form the regulatory subunit of PI 3-kinase potentiated the expression of MMP-9 induced by IL-1 or TNF-alpha. Taken together, these results suggest that PI 3-kinase may act as a negative regulator of MMP-9 expression in C6 glioma cells.
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PMID:Induced expression of MMP-9 in C6 glioma cells is inhibited by PDGF via a PI 3-kinase-dependent pathway. 1220 Jan 27

In the United States, tumors of the central nervous system remain the third leading cancer-related cause of death in young adults with a median survival time of < 1 year. A recent case study suggested that Capecitabine (a novel, fluoropyrimidine prodrug) may be effective in the treatment of brain metastases. Pharmacogenomic studies have correlated the antitumor response to Capecitabine with the expression of the drug metabolizing enzymes thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). In the current study, we examined TP and DPD expression in normal human brain tissues and in glioblastoma multiforme, the most common and malignant type of brain tumor. Because previous reports suggest a tumor necrosis factor (TNF)-alpha-mediated increase in TP expression after irradiation (a current standard of care for glioblastoma multiforme), we also examined the effect of irradiation on the expression of TP, DPD, and TNF-alpha in both irradiated and lead-shielded contralateral U87MG glioma xenografts within the same animal. Expression levels were determined using real-time quantitative PCR as described previously. Results demonstrate an approximately 70-fold increase in TP mRNA levels 4 days after irradiation, relative to initial control levels. Interestingly, TP mRNA in the lead-shielded tumors (contralateral to irradiated tumors) increased approximately 60-fold by day 10 relative to initial control levels. Elevated TP levels were sustained for 20 days in irradiated xenografts but began to decrease after 15 days in the shielded/contralateral tumors, returning to baseline by 20 days. TP mRNA levels in normal mouse liver were unaltered, suggesting a tumor-associated effect. TNF-alpha mRNA levels did not increase after irradiation; therefore, mRNA expression of 11 additional cytokines [interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, and IFN-gamma] in both the irradiated and shielded xenografts was quantitated. Results demonstrated increased levels of IFN-gamma, IL-10, and IL-1 alpha by 6.3-, 3.7-, and 1.6-fold, respectively, in irradiated tumors only. DPD mRNA levels did not change after irradiation. The tumor-associated induction of TP in irradiated and lead-shielded tumors within the same animal may have significant implications for the combined modality treatment of cancer patients with Capecitabine in conjunction with radiotherapy and may apply to the treatment of distant tumors and or metastatic disease.
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PMID:Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: implications for a dual modality treatment using capecitabine and irradiation. 1248 38


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