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

The inhibition by IFN-beta of acquired resistance to the epipodophillotoxin etoposide was studied using a human glioblastoma cell line, T98G. T98G cells were exposed to either etoposide alone or both etoposide and IFN-beta, and after subculture, the same two series of drug exposure were repeated. Degree of level of resistance was tested by the response of the cells to etoposide and changes in their DNA histograms. Furthermore, topoisomerase II in each set of cells was subjected to fluorescence staining with monoclonal anti-topoisomerase II antibody, and the amount of fluorescence was measured by flow cytometry. Secondary etoposide exposure showed less cytotoxicity when the first exposure was to etoposide alone. In contrast, the cytotoxicity was almost the same as that after the first exposure when IFN-beta was added. Resistance to etoposide may result from qualitative or quantitative alterations in the target enzyme, topoisomerase II. The present results show that resistant cells have less topoisomerase II than sensitive cells, suggesting that IFN-beta inhibits the acquisition of resistance to etoposide by suppressing the alteration in topoisomerase II. The inhibition of acquired resistance to etoposide by IFN-beta suggests that continuous and repeated chemotherapy for glioblastoma and other malignant tumors may be clinically advantageous.
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PMID:IFN-beta inhibition of etoposide resistance acquisition in vitro: studies using a human glioblastoma cell line. 776 95

There are three types of interferons (IFN), alpha, beta and gamma. IFN-alpha is produced in the leukocytes infected with virus, while IFN-beta is from fibroblasts infected with virus. IFN-gamma is induced by the stimulation of sensitized lymphocytes with antigen or non-sensitized lymphocytes with mitogens. It is believed that IFN-alpha and beta originated from the same ancestral gene, whereas IFN-gamma did not. IFN has not only an antiviral activity, but also various kinds of biological activities including cell growth inhibition, immunosuppressive effects, enhancement of macrophage, natural killer (NK) cell, killer (K) cell and neutrophil functions, and cell differentiation-inducing activity. IFN also shows the antitumor activity resulting from the integration of the above-mentioned biological activities. IFN is also deeply involved in the pathogenesis of various diseases, e.g., collagen diseases such as SLE and rheumatoid arthritis, insulin-dependent diabetes mellitus, fulminant hepatitis, severe pancreatitis, nephritis, multiple sclerosis, allergic diseases, and atherosclerosis. At present, IFN is clinically used in therapy against virus infections such as hepatitis B and C, and for malignancies such as renal cell carcinoma, multiple myeloma, malignant melanoma, glioblastoma, skin cancers, malignant lymphoma and chronic myelogenous leukemia.
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PMID:[Interferon-alpha, beta, gamma]. 799 28

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

Southern blot analyses of the 9p-localized type I interferon (IFN) genes in DNAs obtained from malignant glioma cell lines and glial tumor tissue have indicated that homozygous deletions of the IFN-alpha and IFN-beta genes often occur during the development of the highly malignant central nervous system neoplasm, glioblastoma. We have applied a set of markers that span the IFN region on 9p to the analysis of DNAs from 30 human glioma cell lines in order to define the region of homozygous deletion associated with this cancer more precisely. Fourteen of the cell lines revealed either complete (12 cases) or partial (2 cases) homozygous deletions of the IFN-alpha gene cluster; no instances of homozygous deletions were observed that did not involve the IFN-alpha region. Genomic DNA identified by the markers nearest to and flanking the IFN-alpha genes were retained in 5 of the cases with homozygous deletions. Consequently, these results limit the extent of homozygous deletions in glioma cell lines to a small region of 9p21-p22 that includes most of the type I IFN locus.
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PMID:Localization of chromosome 9p homozygous deletions in glioma cell lines with markers constituting a continuous linkage group. 833 74

In this study, we examined the clinical course and prognosis of 32 patients with malignant glioma (17 patients with anaplastic astrocytoma, 15 patients with glioblastoma) treated with the MIC regimen (radiation, MCNU, carboplatin and IFN-beta) or MICE regimen (radiation, MCNU, carboplatin, etoposide and IFN-beta). Ten patients were treated with the MIC regimen and 22 patients with the MICE regimen. The patients treated with the MIC and MICE regimens exhibited no significant difference in clinical background factors. The response rate was 50.0% among the 8 evaluable patients treated with the MIC regimen, and 40.0% among the 20 evaluable patients treated with the MICE regimen. The first- and second-year survival rates for the MIC regimen were 40.0% and 30.0%, and those for the MICE regimen were 68.2% and 36.4%. The overall first- and second-year survivals were 59.4% and 33.9%, respectively. The 50% survival time was 8.6 months for the MIC regimen, 14.9 months for the MICE regimen, and 13.4 months overall. There was no significant difference in response rate or survival period between the group treated with the MIC regimen and that treated with the MICE regimen. Age, histological grade of malignancy, radicality of surgery and total dose of irradiation did not affect length of survival. The only factors significantly related to length of survival were response to the induction therapy and performance of maintenance therapy. These results did not demonstrate the superiority of either the MIC or MICE regimen to other regimens previously reported for the treatment of glioma. In addition, etoposide was found not to improve the efficacy of this type of combined chemoradiation therapy.
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PMID:[A clinical evaluation of combination therapy with radiation, MCNU, carboplatin and IFN-beta or with radiation, MCNU, carboplatin, etoposide and IFN-beta for malignant gliomas]. 983 7

In order to analyse immune-stimulatory effects of infection of human tumor cells with Newcastle Disease Virus (NDV), gamma-irradiated human breast carcinoma, colon-carcinoma or glioblastoma cells from defined cell lines were modified either by true infection with live virus or by cell surface adsorption of UV-inactivated replication deficient virus. Modification with live but not inactive NDV induced in all human tumor cells IFN-beta and the chemokines RANTES and IFN-gamma-inducible protein-10 (IP-10). In addition, infection by live NDV induced upregulation of HLA-ABC-molecules in all tumor lines tested and HLA-DR molecules in breast carcinoma lines. Two cell adhesion molecules, ICAM-I (CD54) and LFA-3 (CD58), were also upregulated on human tumor cells after infection with live NDV. When infection of MCF-7 breast carcinoma cells by NDV was performed in the presence of neutralizing anti-IFN-beta antibodies no upregulation of HLA molecules was observed suggesting an important role of IFN-beta in this process. Forty-eight to 72 hours after infection of the irradiated tumor cells with live NDV, many tumor cells were dead or in early or late stages of apoptosis. These results provide explanations for the function of the virus-modified autologous tumor vaccine ATV-NDV with which promising clinical results have already been obtained.
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PMID:Human tumor cell infection by Newcastle Disease Virus leads to upregulation of HLA and cell adhesion molecules and to induction of interferons, chemokines and finally apoptosis. 1206 54

The precise mechanisms governing the direct effect of IFN-beta, including apoptosis induction, are not yet fully understood. To gain a better insight into these mechanisms, we investigated the signaling pathways focusing particularly on interferon regulatory factor 1 (IRF-1) and IRF-2 in glioblastoma cell lines. Furthermore, we attempted to determine whether or not IRF-1 and IRF-2 act as additional prognostic indicators in diffusely infiltrating astrocytomas (DIA). We first assessed the cytotoxic effects of IFN-beta based on a cell growth study and modified MTT assay, and then quantified the apoptosis using a sandwich enzyme immunoassay following IFN-beta treatment in the cell lines, U-87MG, T98G, and A-172. Subsequently, we carried out an analysis of apoptosis-related molecules as evaluated by densitometric analysis of Western blots, focusing on IRF-1 and IRF-2, and two major initiator caspases, caspase-8 and caspase-9. Furthermore, we assessed the expression of type I IFN receptor, IRF-1, and IRF-2 using immunohistochemical techniques in 63 DIA (15 of WHO grade II, 18 of grade III, and 30 of grade IV), and analyzed their impact on prognosis. An increase in apoptosis was apparent after 48 h of IFN-beta treatment (1 x 10(4) IU/ml) in T98G but not in U-87MG or A-172. IFN-beta treatment for 6 h significantly enhanced the expression of IRF-1 in all three cell lines. However, an enhanced expression of IRF-2 was observed only in the not-most-sensitive, non-apoptosis-induced U-87MG and A-172. While minimal processing of caspase-8 was noted in the three cell lines throughout the experiment, caspase-9 activation was observed in the apoptosis-detected T98G after 48 h of treatment, as indicated by a 1.33-fold increase (P=0.037). On the other hand, the IRF-1 LI and IRF-1/IRF-2 LI ratio were greater in low-grade DAI, and were negatively correlated with the histopathological grade in DIA (P=0.017 and P=0.001, respectively). Furthermore, the IRF-1/IRF-2 LI ratio was negatively correlated with the MIB-1 LI in DIA (P=0.004), and represented an independent and most powerful determinant of overall survival compared to other conventional prognostic factors (P=0.018). However, the relation was not statistically significant when only patients with high-grade DIA were assessed. Our findings suggest that up-regulation of IRF-1 and IRF-2 might be an important determinant of susceptibility to IFN-beta mediated cytotoxicity including apoptosis. Furthermore, the IRF-1/IRF-2 LI ratio may reflect the proliferative state of DIA and constitute an important prognostic marker in DIA. Thus, IRF-1 and IRF-2 could represent one of the therapeutic target sites for the regulation of cell growth in DIA.
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PMID:Therapeutic implications of interferon regulatory factor (IRF)-1 and IRF-2 in diffusely infiltrating astrocytomas (DIA): response to interferon (IFN)-beta in glioblastoma cells and prognostic value for DIA. 1618 22

Glioblastoma multiforme (GBM) is the most aggressive type of all primary brain tumors, with an overall median survival <1 year after diagnosis. Despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the past 50 years. In this study we investigated the effect of intracerebroventricular (ICV) injection of an adeno-associated virus (AAV) vector encoding human interferon-beta (AAV-hIFN-beta) on glioblastoma growth. Recently, we found that peritumoral parenchymal transduction with an AAV-hIFN-beta was exceptionally efficient in eradicating GBM brain tumors. However, the extensive infiltration and migration displayed by glioblastoma cells in patients may leave a significant number of tumor cells outside a local therapeutic zone created by intraparenchymal delivery of AAV vectors. Here we show that pretreatment of mice by ICV infusion of an AAV-IFN-beta completely prevents tumor growth in an orthotopic model of GBM. Furthermore, ICV infusion of AAV-IFN-beta into mice bearing preestablished U87 intracranial tumors improved their survival compared to mice infused through the same route with a control AAV vector. These data suggest that ICV injection of AAV vectors encoding antitumor proteins is a promising approach deserving further consideration for the treatment of GBM.
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PMID:Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-beta. 1919 27

Malignant glioma is one of the most aggressive cancers. For the development of effective therapeutic strategies against such malignant diseases, elucidation of molecular targets is necessary. We found that inactivated Sendai virus particle (HVJ-E) induced extensive cell death in the human glioblastoma cell line U251MG. Intradermal U251MG tumors were more effectively suppressed by HVJ-E than interferon (IFN)-beta. From microarray analysis of gene expression in U251MG cells treated with HVJ-E, we focused on the up-regulation of sterile alpha motif containing domain 9 (SAMD9) gene. The expression of the SAMD9 gene was induced by administration of recombinant human IFN-alpha, -beta or -gamma. The up-regulation of the SAMD9 gene by HVJ-E treatment was abrogated by IFN receptor blocking antibody or JAK inhibitor treatment. When SAMD9 expression was knocked down by RNA interference, apoptotic cell death induced by HVJ-E was blocked in U251MG cells. Suppression of SAMD9 using SAMD9 siRNA also inhibited IFN-beta-induced death in U251MG cells with a small, but significant, difference to control groups. However, overexpression of the SAMD9 gene failed to induce significant cell death in U251MG cells. Thus, SAMD9 could be a key molecule to control cancer cell death by HVJ-E or IFN-beta treatment.
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PMID:Sterile alpha motif containing domain 9 is involved in death signaling of malignant glioma treated with inactivated Sendai virus particle (HVJ-E) or type I interferon. 1983 Jun 90


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