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)

CD95 (Fas/APO-1) and its ligand (CD95L) belong to a growing cytokine and cytokine receptor family that includes nerve growth factor (NGF) and tumor necrosis factor (TNF) and their corresponding receptors. CD95 expression increases during malignant progression from low-grade to anaplastic astrocytoma and is most prominent in perinecrotic areas of glioblastoma. There is, however, no evidence that CD95 expression in malignant gliomas is triggered by hypoxia or ischemia. Agonistic antibodies to CD95, or the natural ligand, CD95L, induce apoptosis in human malignant glioma cells in vitro. Glioma cell sensitivity to CD95-mediated apoptosis is regulated by CD95 expression at the cell surface and by the levels of intracellular apoptosis-regulatory proteins, including bcl-2 family members. Several cytotoxic drugs synergize with CD95L to kill glioma cells. For as yet unknown reasons, glioma cells may co-express CD95 and CD95L in vitro without undergoing suicide or fratricide. Yet, they kill T cells via CD95/CD95L interactions and are sensitive to exogenously added CD95L. Since CD95L is expressed in gliomas in vivo, too, forced induction of CD95 expression might promote therapeutic apoptosis in these tumors. That glioma cells differ from nontransformed T cells in their sensitivity to CD95 antibodies or recombinant ligand, may allow the development of selective CD95 agonists with high antitumor activity that spare normal brain tissue. A family of death ligand/receptor pairs related to CD95L/CD95, including APO2L (TRAIL) and its multiple receptors is beginning to emerge. Although several issues regarding glioma cell sensitivity to CD95L/CD95-mediated apoptosis await elucidation, CD95 is a promising target for the treatment of malignant glioma.
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PMID:CD95 ligand: lethal weapon against malignant glioma? 954 87

We have previously demonstrated that a human glioblastoma cell line, T98G cells, produced high levels of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) when stimulated with IL-1 or tumor necrosis factor-alpha (TNF-alpha). In this study, we found that T98G cells are capable of producing large amounts of IL-8 and MCP-1 when cocultured with human peripheral blood monocytes or a monocytic cell line, U937 cells. Since it is possible that both glioblastoma cells and monocytes are capable of producing chemokines, we determined which type of cells actually produced IL-8 and MCP-1, by the fixation of one or the other cell type with 3% paraformaldehyde (PA). This procedure revealed that T98G cells were the main source and that PA-treated monocytes effectively stimulated IL-8 and MCP-1 production by T98G cells. Both IL-8 and MCP-1 gene expression and protein production by T98G cells were confirmed by northern blot as well as immunohistochemical staining methods. To analyze the molecules on human monocytes responsible for inducing IL-8 and MCP-1 by T98G cells, several antibodies (Abs) as well as IL-1 receptor antagonist (IL-1Ra) were tested. Anti-IL-1alpha Ab and IL-1Ra almost completely abolished the IL-8/MCP-1-inducing capacity of the PA-fixed monocytes, while no inhibition was obtained with anti-IL-1beta, anti-TNF-alpha or Abs against CD11b/18, L-selectin or ICAM-1, indicating that membrane-associated IL-1alpha is involved in the IL-8/MCP-1 induction, while secreted IL-1alpha plays a major role in this cell-to-cell, i.e., juxtacrine interaction in unfixed conditions.
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PMID:Interleukin-8 and monocyte chemotactic protein-1 production by a human glioblastoma cell line, T98G in coculture with monocytes: involvement of monocyte-derived interleukin-1alpha. 961 77

Cells of a human glioblastoma line were stably transfected with a glial fibrillary acidic protein (GFAP) promoter sequence/lacZ reporter gene. Following this modification, they produced Escherichia coli beta-galactosidase constitutively in amounts that could be measured through their conversion of an added fluorophore into a product readily estimated by fluorimetry. Human interferons (IFN) selectively and in a dose-dependent manner reduce the formation of beta-galactosidase in this system. We have used it as the basis for a novel assay that is sensitive (4-40 pg/ml), precise, completed in 30 h, and applicable to both type I and type II human IFNs. Statistical analysis showed interassay relative standard deviations ranging from 5% to 11%, and most individual assays revealed potencies with limits of error within 85%-115%. Neither partially trypsin-digested IFN nor the other cytokines and mitogens we tested reacted in this system, except for tumor necrosis factor-alpha (TNF-alpha). The high selectivity was further shown by the loss of response to IFN in the presence of the appropriate specific anti-IFN or anti-IFN-gamma receptor antibodies.
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PMID:The beta-gal interferon assay: a new, precise and sensitive method. 971 60

We present our experience with a combination chemotherapy regimen consisting of ranimustine (MCNU) and recombinant human mutant tumor necrosis factor-alpha (TNF-SAM2) for malignant astrocytomas. The initial regimens were prescribed as adjuvant therapy in conjunction with radiotherapy following standard surgical treatment. Newly diagnosed patients were treated with up to four cycles of this regimen (TNF-SAM2, MCNU, and radiotherapy: TMR group). Seventeen patients (11 men and 6 women) aged 24 to 68 years (median 54.6 years) were eligible and evaluated for response and toxicity. The estimated median survival time was 354 weeks with anaplastic astrocytomas, and 76 weeks with glioblastomas. One- and 2-year survival rates were 100% and 100% with anaplastic astrocytomas, and 69.2% and 29.7% with glioblastomas. Grade 3 and 4 hematological toxicities were not experienced. None of the patients experienced a treatment delay due to toxicity. All other acute toxicities were anticipated and manageable. Twenty three patients (11 men and 12 women) aged 22 to 66 years (median 50.7 years) were evaluated as a historical control of patients who received chemotherapy with MCNU alone in conjunction with radiotherapy following standard surgical treatment (MCNU and radiotherapy: MR group). The estimated median survival time was 205 weeks with anaplastic astrocytomas, and 62 weeks with glioblastomas. One- and 2-year survival rates were 88.9% and 66.7% with anaplastic astrocytomas, and 71.4% and 7.1% with glioblastomas in this group. There were no significant differences in survival rates between patients in the TMR and MR groups with either anaplastic astrocytoma or glioblastoma. However, despite the small number of patients, those with anaplastic astrocytoma in the TMR group tended to survive longer than those in the MR group. These results suggest that combined chemotherapy with mutant TNF-alpha may benefit those with anaplastic astrocytoma, and thus warrants further evaluation. On the other hand, the lack of activity does not warrant any further study of this schedule of TNF-SAM2 for the treatment of glioblastoma.
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PMID:Treatment of malignant astrocytomas with recombinant mutant human tumor necrosis factor-alpha (TNF-SAM2). 985 11

Human SK-N-AS neuroblastoma and U-87MG glioblastoma cell lines were found to secrete relatively high levels of glial cell line-derived neurotrophic factor (GDNF). In response to growth factors, cytokines, and pharmacophores, the two cell lines differentially regulated GDNF release. A 24-hr exposure to tumor necrosis factor-alpha (TNFalpha; 10 ng/ml) or interleukin-1beta (IL-1,; 10 ng/ml) induced GDNF release in U-87MG cells, but repressed GDNF release from SK-N-AS cells. Fibroblast growth factors (FGF)-1, -2, and -9 (50 ng/ml), the prostaglandins PGA2, PGE2, and PGI2 (10 microM), phorbol 12,13-didecanoate (PDD; 10 nM), okadaic acid (10 nM), dexamethasone (1 microM), and vitamin D3 (1 microm) also differentially effected GDNF release from U-87MG and SK-N-AS cells. A result shared by both cell lines, was a two- to threefold increase in GDNF release by db-cAMP (1 mM), or forskolin (10 microM). In general, analysis of steady-state GDNF mRNA levels correlated with changes in extracellular GDNF levels in U-87MG cells but remained static in SK-N-AS cells. The data suggest that human GDNF synthesis/release can be regulated by numerous factors, signaling through multiple and diverse secondary messenger systems. Furthermore, we provide evidence of differential regulation of human GDNF synthesis/release in cells of glial (U-87MG) and neuronal (SK-N-AS) origin.
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PMID:Differential regulation of glial cell line-derived neurotrophic factor (GDNF) expression in human neuroblastoma and glioblastoma cell lines. 997 21

The effectiveness of chemotherapy for human cancers is limited by pharmacokinetic parameters such as variation in metabolism and is determined by the cellular response. In this work, we aimed to gain a more holistic understanding of the molecular basis of glioma response to the DNA-alkylating agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by using a systematic approach: we investigated the expression of 588 genes with various cellular functions in a BCNU-resistant glioblastoma cell line and a BCNU-sensitive subline before and after treatment with BCNU. Our gene expression profiling revealed major differences in gene expression between these two cell lines, especially after treatment with BCNU. One striking example was that BCNU decreased the expression of six DNA-repair genes in sensitive but not in resistant cells. In sensitive cells, BCNU treatment resulted in the induction of two MAP kinase genes; this finding suggests that the specific response to BCNU in sensitive cells may involve the Jun kinase signal transduction pathway. After BCNU treatment, marked induction of tumor necrosis factor was detected only in sensitive cells, suggesting that tumor necrosis factor is a mediator of BCNU-induced cell death. Bcl-2 family members were not altered by BCNU in sensitive cells, suggesting that BCNU-induced cell death may be independent of the bcl-2 pathway. Results of the present study demonstrate that gene expression profiling may facilitate identification of cellular pathways associated with specific responses to chemotherapeutic agents and contribute to an understanding of the molecular basis of drug action.
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PMID:Characterization of cellular pathways involved in glioblastoma response to the chemotherapeutic agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by gene expression profiling. 1002 10

We investigated whether matrix metalloproteinase-2 (MMP-2) is induced in peripheral blood T cells after their contact with tumor necrosis factor-alpha (TNF-alpha)-stimulated glioblastoma cell line (T98G), expressing vascular cell adhesion molecule-1 (VCAM-1), in patients with HTLV-I-associated myelopathy (HAM) compared to control patients with other neurological disorders (OND). Gelatin zymography revealed that the incremental ratio of gelatinolytic activity of MMP-2 in culture supernatants derived from T cells cocultured with TNF-alpha-stimulated T98G to that of supernatants derived from cultures of T cells alone was significantly higher in HAM patients than in control patients with OND. Immunoblot analysis of immunoprecipitates of culture supernatant showed that increased gelatinolytic activity of MMP-2 was due to increased production of MMP-2 protein in T cells. Increased gelatinolytic activity of MMP-2 in T cells of HAM patients was blocked by pretreatment of TNF-alpha-stimulated T98G with anti-VCAM-1 antibody before coculture with T cells, indicating that MMP-2 induction was VCAM-1-mediated. Although no significant differences were noted in the percentage of VLA-4-positive cells in cultured T cells between HAM patients and control patients with OND, our results indicate that VCAM-1-mediated MMP-2 induction is up-regulated in T cells of HAM patients.
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PMID:Vascular cell adhesion molecule-1-mediated matrix metalloproteinase-2 induction in peripheral blood T cells is up-regulated in patients with HTLV-I-associated myelopathy. 1050 81

The intractability of malignant gliomas to multimodality treatments plays a large part in their extremely poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel member of the tumor necrosis factor (TNF) family that induces apoptosis preferentially in tumor cells through binding to its cognate death receptors, DR4 and DR5. Here we show that the DNA-damaging chemotherapeutic drugs, cis-diamminedichloroplatinum(II) (CDDP) and etoposide, elicited increased expression of DR5 in human glioma cells. Exposure of such cells in vitro to soluble human TRAIL in combination with CDDP or etoposide resulted in synergistic cell death that could be blocked by soluble TRAIL-neutralizing DR5-Fc or the caspase inhibitors, Z-Asp-CH2-DCB and CrmA. Moreover, systemic in vivo administration of TRAIL with CDDP synergistically suppressed both tumor formation and growth of established s.c. human glioblastoma xenografts in nude mice by inducing apoptosis without causing significant general toxicity. The combination treatment resulted in complete and durable remission in 29% of mice with the established s.c. xenografts and also significantly extended the survival of mice bearing intracerebral xenografts. These results provide preclinical proof-of-principle for a novel therapeutic strategy in which the death ligand, TRAIL, is safely combined with conventional DNA-damaging chemotherapy.
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PMID:Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. 1070 92

BACKGROUND: Antisense oligodeoxynucleotides (ODNs) have been proposed as a new therapy for patients with cancer, including malignant brain tumors. Antisense ODNs are taken up by tumor cells and selectively block gene expression. Use of ODNs for brain tumors is attractive due to their theoretical specificity, relative ease of production and, to date, paucity of reported adverse effects. This article presents current information regarding antisense ODNs and their possible future use for the treatment of brain tumors. METHODS: The available published experimental and clinical information regarding antisense ODN treatment of glioblastoma cells and administration into the central nervous system (CNS) was reviewed. Other clinically relevant information pertaining to the molecular biology of antisense ODNs was also collected and summarized. RESULTS: Targets for antisense ODN therapy in malignant glioma cells have included c-myc, c-myb, c-sis, c-erb B, CD44, p34cdc2, bFGF, PDGF, TGF-beta, IGF-1, PKC-alpha tumor necrosis factor, urokinase, and S100beta protein. Few in vivo studies of ODN treatment of brain tumors have yet been reported. Systemically administered ODNs enter the brain only in extremely small quantities; therefore, microinfusion into the brain has been recommended. CONCLUSIONS: Antisense ODNs have been used successfully to block glioblastoma gene expression in vitro and expression of multiple genes within the CNS of experimental animals. Upcoming clinical trials will address the safety of antisense ODN use against malignant brain tumors.
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PMID:Antisense Oligodeoxynucleotide Technology: Potential Use for the Treatment of Malignant Brain Tumors. 1076 Oct 27

We present our experience with a combination chemotherapy regimen consisting of ranimustine (MCNU) and recombinant human mutant tumor necrosis factor-alpha (TNF-SAM2) for malignant astrocytomas. We also investigated the expression of nuclear factor-kappa B (NF-kappa B), tumor necrosis factor receptor type 1 (TNFR1), and c-Myc in human astrocytoma tissues in vivo in patients treated with TNF-SAM2 by RT-PCR and immunohistochemical analysis to examine whether there is any correlation between the prognosis of these patients after TNF-SAM2 treatment and the expression of these factors. The initial regimens were prescribed as adjuvant therapy in conjunction with radiotherapy following standard surgical treatment. Newly diagnosed patients were treated with up to four cycles of this regimen (TNF-SAM2, MCNU, and radiotherapy: TMR group). Four patients with anaplastic astrocytomas and 13 patients with glioblastomas (11 men and 6 women) aged 24 to 68 years (median 55.7 years) were eligible and evaluated for response and toxicity. The estimated median survival time was 354 weeks with anaplastic astrocytomas, and 79 +/- 10.8 weeks with glioblastomas. One- and 2-year survival rates were 100% and 100% with anaplastic astrocytomas, and 69.2% and 30.8% with glioblastomas. Grade 3 and 4 hematological toxicities were not experienced. None of the patients experienced a treatment delay due to toxicity. All other acute toxicities were anticipated and manageable. Two of the 4 patients with anaplastic astrocytomas were positive for the expression of NF-kappa B, TNFRl and c-Myc. The expression of NF-kappa B, TNFR1 and c-Myc was investigated in 10 of the 13 patients with glioblastoma, and c-Myc, TNFRl and NF-kappa B were detected in 9, 7, and 8 of these 10 patients' surgical specimens, respectively. Despite the small number of patients, these clinical results suggest that combined chemotherapy with mutant TNF-alpha (TNF-SAM2) was safe and well tolerated, and may confer a survival benefit for patients with malignant astrocytomas in comparison to our historical controls. Its effectiveness as an adjuvant therapy deserves a properly stratified randomized trial. Although there was no significant correlation between the efficacy of TNF-SAM2 treatment and the expression of NF-kappa B, our results suggest that the constitutive activation of NF-kappa B subunits in malignant astrocytomas, especially in glioblastoma, could be associated with resistance to TNF-alpha immunotherapy. These results could offer new insight to help establish a new chemotherapeutic strategy for malignant astrocytomas.
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PMID:Correlation of the expression of nuclear factor-kappa B, tumor necrosis factor receptor type 1 (TNFR 1) and c-Myc with the clinical course in the treatment of malignant astrocytomas with recombinant mutant human tumor necrosis factor-alpha (TNF-SAM2). 1076 4


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