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)

Seven patients with recurrent high-grade glioma were treated in a Phase I/II trial with surgical debulking, after which mitogen-activated IL-2-stimulated killer (MAK) lymphocytes and 10(5) units rIL-2 were implanted in the surgical defect. The therapy was well tolerated, and the mean survival of this group of patients was 29 weeks. Tumor necrosis factor (TNF) production by MAK lymphocytes stimulated with IL-2 in vitro was measured. A significant (r = .78, p = .04) correlation between survival of patients after therapy and the ability of the MAK lymphocytes to produce TNF in vitro was noted. A significant negative correlation (r = -.82, p = .02) was found when comparing TNF production and increasing tumor size measured on MRI. No correlation was found between TNF production in vitro and MAK lymphocytes lytic activity on K562 and U373 target cells. No correlation was found between survival and MAK cell lytic activity measured on K562 and U373 target cells. We conclude that TNF production in vitro and cytotoxic activity measured in vitro are measures of different antitumor activity in vivo and in vitro. TNF production during IL-2-stimulated proliferation may be an important in vitro assay in terms of predicting length of survival of recurrent high-grade gliomas.
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PMID:Therapy of recurrent high-grade gliomas with surgery, autologous mitogen-activated IL-2-stimulated (MAK) killer lymphocytes, and rIL-2: II. Correlation of survival with MAK cell tumor necrosis factor production in vitro. 187 60

Tumor necrosis factor (TNF)-alpha gene were transfected into lymphokine-activated killer (LAK) cells generated from peripheral blood lymphocytes incubated with recombinant interleukin-2 by means of novel liposomes with a positive charge on their surface. The cells secreted significant amounts of TNF-alpha into the culture medium and exhibited reinforcement of cytotoxicity toward a human glioma cell line (U251-SP), being three times more cytotoxic than nontransfected LAK cells. The mechanism for the reinforcement of cytotoxicity is considered to involve not only an increase in TNF-alpha secretion from LAK cells but also its expression on their surface. Intratumoral or intrathecal injection of LAK cells transfected with the TNF-alpha gene may be useful for the treatment of patients with malignant glioma.
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PMID:[Enhanced anti-tumor effect of lymphokine-activated killer cells transfected with tumor necrosis factor-alpha gene on human glioma cells]. 795 91

Infiltration of the central nervous system (CNS) by monocytes is a characteristic of many non-malignant disease processes, although the signals regulating such traffic are unclear. Tumor necrosis factor (TNF) and other inflammatory cytokines have been shown to elicit production of monocyte chemoattractant activity in glioma cells, but the regulation of such activity in non-neoplastic adult astrocytes has not been examined. We previously observed that TNF constituted a proliferative signal for non-neoplastic adult human astrocytes in vitro involving the 55-kDa TNF receptor. In the present study, we demonstrate that TNF exposure enhances the expression of monocyte chemoattractant protein-1 (MCP-1) mRNA and functional monocyte chemoattractant activity in non-neoplastic astrocytes. Results indicated that MCP-1 mRNA expression was maximal within 3 h, and was further augmented by the protein synthesis inhibitor cycloheximide (CY). Antibody (htr-9) directed against the 55-kDa TNF receptor also elicited MCP-1 mRNA expression while antibody to the 75-kDa TNF receptor (utr-1) was ineffective. Secretion of monocyte chemoattractant activity was significantly greater in TNF- or htr-9-treated astrocytes than in utr-1-treated or untreated controls; activity was abolished by treatment with antibody to MCP-1. These findings suggest that non-neoplastic adult human astrocytes may contribute to CNS inflammatory responses by mediating recruitment of peripheral blood monocytes.
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PMID:Regulation of monocyte chemoattractant protein-1 expression in adult human non-neoplastic astrocytes is sensitive to tumor necrosis factor (TNF) or antibody to the 55-kDa TNF receptor. 830 Aug 51

Tumor necrosis factor (TNF)-alpha has been shown to exert cytotoxic or cytostatic effects on tumor cells, but susceptibility to TNF-alpha varies among different types of cells. TNF-alpha activates a transcription factor, nuclear factor-kappaB (NF-kappaB), which induces a wide variety of genes and causes pleiotrophic responses. In this study, the relationship between susceptibility to TNF-alpha and activation of NF-kappaB was investigated in six human malignant glioma cell lines. Cell proliferation analysis revealed that only one cell line, SK-MG-1, was sensitive to TNF-alpha and that the other five, including U-251MG, were resistant. Electrophoretic mobility-shift assay showed that TNF-alpha strongly activated a subtype of NF-kappaB, the p50-p65 heterodimer, in all of the resistant cell lines tested. However, this activation was weak in the sensitive cell line, SK-MG-1. Activation of NF-kappaB by TNF-alpha in the resistant cell lines resulted in a significant increase of a reporter gene expression driven by NF-kappaB site, suggesting a possibility that activation of p50-p65 confers resistance to TNF-alpha. To test this hypothesis, we established a stable cell line that expresses an inducible dominant negative NF-kappaB (p65 DN) protein in one of the TNF-alpha-resistant cell lines, U-251MG. In the established clone, induction of p65 DN protein decreased TNF-alpha-dependent increase in the DNA binding of p50-p65 heterodimer and NF-kappaB-dependent reporter gene activity. Although no growth inhibition of this clone was observed by TNF-alpha treatment, induction of p65 DN together with TNF-alpha resulted in a significant decrease in cell number. Cell cycle analysis revealed that this growth inhibition was due to the impairment of cell cycle progression. These results indicate that an active NF-kappaB complex, such as the p50-p65 heterodimer, plays a crucial role in the progression of cell cycle in malignant glioma cells. Refractoriness to TNF-alpha treatment could be prevented by inhibiting NF-kappaB activation.
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PMID:Inhibition of nuclear factor-kappaB activation confers sensitivity to tumor necrosis factor-alpha by impairment of cell cycle progression in human glioma cells. 1048 96

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

Tumor necrosis factor-alpha (TNF), which was initially supposed to be a promising cancer therapeutic reagent, does not kill most types of cancer cells partly due to the activation of an anti-apoptotic gene, NF-kappaB. NF-kappaB forms an inactive complex with the inhibitor kappa B alpha (IkappaBalpha), which is rapidly phosphorylated and degraded in response to various extracellular signals. To disrupt this protective mechanism, we introduced an inhibitor kappa B alpha (IkappaBdN) gene, a deletion mutant gene lacking the nucleotides for the N-terminal 36 amino acids of IkappaBalpha, into human glioma cells (U251, T-98G, and U-373MG) via an adenoviral (Adv) vector in addition to treatment of the glioma cells with recombinant TNF. Immunohistochemical analysis revealed that NF-kappaB was translocated to nuclei by TNF treatment in U251 and T-98G cells, but not in U-373MG cells. Neither transduction of IkappaBdN nor treatment with TNF protein alone induced apoptosis in U251 and T-98G cells, whereas both cell lines underwent drastic TNF-induced apoptosis after transduction of IkappaBdN. On the other hand, U-373MG cells were refractory to TNF-induced apoptosis even when they were transduced with the IkappaBdN gene. U-373MG cells underwent drastically increased apoptosis when co-transduced with the IkappaBdN and Bax gene in the presence of TNF. Adv-mediated transfer of IkappaBdN or IkappaBdN plus Bax may be a promising therapeutic approach to treat gliomas through TNF-mediated apoptosis.
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PMID:Adenovirus-mediated gene transduction of IkappaB or IkappaB plus Bax gene drastically enhances tumor necrosis factor (TNF)-induced apoptosis in human gliomas. 1074 43

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells, thus providing a therapeutic potential. In this study, we examined a large panel of human malignant glioma cell lines and primary cultures of normal human astrocytes for their sensitivity to TRAIL. Of 13 glioma cell lines, 3 were sensitive (80-100% death), 4 were partially resistant (30-79% death), and 6 were resistant (< 30% death). Normal astrocytes were also resistant. TRAIL-induced cell death was characterized by activation of caspase-8 and -3, poly(ADP-ribose) polymerase cleavage, and DNA fragmentation. Decoy receptor (DcR1 and DcR2) expression was limited in the glioma cell lines and did not correlate with TRAIL sensitivity. Both sensitive and resistant cell lines expressed TRAIL death receptor (DR5), adapter protein Fas-associated death domain (FADD), and caspase-8; but resistant cell lines expressed 2-fold higher levels of the apoptosis inhibitor phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 kDa (PED/PEA-15). In contrast, cellular FADD-like IL-1beta-converting enzyme-like inhibitory protein (cFLIP) expression was similar in sensitive and resistant cells. Transfection of sense PED/PEA-15 cDNA in sensitive cells resulted in cell resistance, whereas transfection of antisense in resistant cells rendered them sensitive. Inhibition of protein kinase C (PKC) activity restored TRAIL sensitivity in resistant cells, suggesting that PED/ PEA-15 function might be dependent on PKC-mediated phosphorylation. In summary, TRAIL induces apoptosis in > 50% of glioma cell lines, and this killing occurs through activation of the DR pathway. This caspase-8-induced apoptotic cascade is regulated by intracellular PED/PEA-15, but not by cFLIP or decoy receptors. This pathway may be exploitable for glioma and possibly for other cancer therapies.
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PMID:Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells. 1122 47

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can trigger apoptosis in some tumor cells but not other tumor cells. To explore the signal transduction events in TRAIL-triggered apoptosis and its modulation in nontransfected tumor cells, we analyzed TRAIL-induced death-inducing signaling complex (DISC) in TRAIL-sensitive and -resistant glioma cells. Caspase-8 and caspase-10 were recruited to the DISC, where they were proteolytically activated to initiate apoptosis in TRAIL-sensitive glioma cells. Caspase-8 and caspase-10 were also recruited to the DISC in TRAIL-resistant cells, but their further activation was inhibited by two antiapoptotic proteins termed cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (c-FLIP) and phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15kDa (PED/PEA-15). Both long and short forms of c-FLIP were recruited to the DISC, where the long form c-FLIP was cleaved to produce intermediate fragments. Of the three isoforms of PED/PEA-15 proteins, only the doubly phosphorylated form was expressed and recruited to the DISC in TRAIL-resistant cells, indicating that the phosphorylation status of PED/PEA-15 determines its recruitment in the cells. Treatment with calcium/calmodulin-dependent protein kinase inhibitor rescued TRAIL sensitivity in TRAIL-resistant cells, providing a potential new approach to sensitize the cells to TRAIL-induced apoptosis.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells. 1197 44

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in neoplastic cells. While many previous studies have been performed in cell culture, the delivery and efficiency of TRAIL variants in vivo is less well established. Using dual substrate/reporter bioluminescence imaging (Fluc: firefly luciferase-luciferin and Rluc: Renilla luciferase-coelenterazine), we tested the efficacy of TRAIL using replication-deficient herpes simplex virus (HSV) type 1 amplicon vectors in gliomas. The cDNA for complete TRAIL and the extracellular domain of TRAIL (aa 114-281) were cloned into HSV amplicons and packaged into helper virus-free vectors. Both forms of TRAIL induced similar degrees of apoptosis in human glioma cells (Gli36) in culture within 24 h of infection with TRAIL amplicon vectors. Growth of tumors stably transfected with Fluc (Gli36fluc+) was readily monitored in vivo by bioluminescence imaging following luciferin administration. HSV amplicon vectors bearing the genes for TRAIL and Rluc injected directly into Gli36fluc(+)-expressing subcutaneous gliomas revealed peak Rluc activity 36 h after intratumoral injection as determined by coelenterazine injection followed by imaging. TRAIL-treated gliomas regressed in size over a period of 4 weeks as compared to the mock-injected gliomas. These results show the efficacy of vector delivered TRAIL in treating tumors in vivo and offer a unique way to monitor both gene delivery and efficacy of TRAIL-induced apoptosis in tumors in vivo in real time by dual enzyme substrate (Rluc/Fluc) imaging.
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PMID:Real-time imaging of TRAIL-induced apoptosis of glioma tumors in vivo. 1453 33

The Fn14 gene encodes a type Ia transmembrane protein that belongs to the tumor necrosis factor receptor superfamily. We recently showed that fibroblast growth factor-inducible 14 (Fn14) is overexpressed in migrating glioma cells in vitro and in glioblastoma multiforme clinical specimens in vivo. To determine the biological role of Fn14 in brain cancer progression, we examined the activity of Fn14 as a potential mediator of cell survival. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-stimulated glioma cells had increased cellular resistance to cytotoxic therapy-induced apoptosis. Either TWEAK treatment or Fn14 overexpression in glioma cells resulted in the activation of NFkappaB and subsequently the translocation of NFkappaB from the cytoplasm to the nucleus. In addition, Fn14 activation induced BCL-XL and BCL-W mRNA and protein levels, and this effect was dependent upon NFkappaB transcriptional activity. Substitution of a putative NFkappaB binding site identified in the BCL-X promoter significantly decreased Fn14-induced transactivation. Furthermore Fn14-induced transactivation of the BCL-X promoter was also diminished by the super-repressor IkappaBalpha mutant, which specifically inhibits NFkappaB activity, and by mutations in the NFkappaB binding motif of the BCL-X promoter. Additionally small interfering RNA-mediated depletion of either BCL-XL or BCL-W antagonized the TWEAK protective effect on glioma cells. Our results suggest that NFkappaB-mediated up-regulation of BCL-XL and BCL-W expression in glioma cells increases cellular resistance to cytotoxic therapy-induced apoptosis. We propose that the Fn14 protein functions, in part, through the NFkappaB signaling pathway to up-regulate BCL-XL and BCL-W expression to foster malignant glioblastoma cell survival. Targeted therapy against Fn14 as an adjuvant to surgery may improve management of invasive glioma cells and advance the outcome of this devastating cancer.
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PMID:The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression. 1561 Nov 30


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