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)

We have studied the effect of induced glial fibrillary acidic protein (GFAP) on motility, cell morphology, and proliferation of two originally GFAP-negative human glioma cell lines. Glioma cell lines U-1242 MG and U-251 MG sp subclone 3A were transfected with a vector system that allows for an inducible GFAP expression. This experimental system creates an "on/off" situation in which GFAP expression is suppressed by tetracycline. Inducible expression of GFAP in the absence of tetracycline was confirmed by immunofluorescence staining and Northern and Western blotting. The study showed that forced GFAP expression resulted in an inhibition of cell motility measured as the phagokinetic track area of individual cells seeded sparsely on a surface covered with gold particles. It also resulted in a change in cell morphology, with extended cell processes, and it was associated with a low fraction of cells in S-phase. We conclude that the down-regulation of GFAP expression that is often seen in gliomas in vivo may be an important parameter of tumor progression related mainly to the motile and thereby invasive properties of malignant glioma cells.
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PMID:Effects of inducible glial fibrillary acidic protein on glioma cell motility and proliferation. 1074 Feb 30

Vascular changes in gliomas were analyzed by implanting fluorescent-labeled glioma 261 cells in the brains of 28 mice. Seven animals were killed each week for 4 weeks. We investigated the expression of angiopoietin-2 (Ang-2) by in situ hybridization and compared it with the distribution of apoptotic cells identified by DNA strand breaks (using the terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling [TUNEL] method) and transmission electron microscopy (TEM). As early as 1 week after implantation, tumor cells accumulated around vessels, which expressed Ang-2 and were TUNEL negative. TEM showed tumor cells adjacent to the vascular cells "lifting up" the normal astrocytic feet processes away from the endothelial cells and disrupting normal pericytic cuffing. After 2 weeks the number of perivascular glioma cells had increased. No increase in the number of blood vessels was detected at this time. Vascular cells remained positive for Ang-2 and rare ones were TUNEL positive. TEM showed closely packed proliferating perivascular tumor cells. After 3 weeks, there was vascular involution with scant zones of tumor necrosis. Ang-2 was still detected in vascular cells, but now numerous vascular cells were TUNEL positive. In addition, TEM showed apoptotic vascular cells. After 4 weeks, there were extensive areas of tumor necrosis with pseudopalisading and adjacent angiogenesis. Ang-2 was detected in vascular cells at the edge of the tumors in the invaded brain and in vessels surrounded by tumor cells. At both 3 and 4 weeks, most of the TUNEL-positive tumor cells lacked morphological features characteristic of apoptosis and displayed features consistent with necrotic cell death as determined by TEM. Only rare tumor cells appeared truly apoptotic. In contrast, the TUNEL-positive endothelial cells and pericytes were round and shrunken, with condensed nuclear chromatin by TEM, suggesting that vascular cells were undergoing an apoptotic cell death. These results suggest that vascular cell apoptosis and involution preceded tumor necrosis and that angiogenesis is a later event in tumor progression in experimental gliomas. Moreover, Ang-2 is detected prior to the onset of apoptosis in vascular cells and could be linked to vascular involution.
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PMID:Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. 1087 35

In recent years, it has become evident that astrocytes harbor functional receptors to many neurotransmitters. including substance P (SP), an undecapeptide belonging to the tachykinin family of neuropeptides. SP is an important stimulus for reactive astrocytes in CNS development, infection and injury, and provides a link for bi-directional interactions between glial cells and neurons. In brain tumors, malignant glial cells originating from astrocytes, via NK1 receptors, are triggered by tachykinins, SP and neurokinin A (NKA), to release soluble mediators, in particular cytokines, and increase their proliferative rate. In this paper, we review the results obtained in in vitro and in vivo studies on the role of SP as an inducer of human glioma responses that may be relevant for tumor progression. In addition, the presence of SP and the expression of NK1 receptors in glioma explants have been examined. We discuss the possible use of selective NK1 receptor antagonists as a therapeutic approach to treat malignant gliomas.
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PMID:The role of tachykinins via NK1 receptors in progression of human gliomas. 1095 33

EMMPRIN (extracellular matrix metalloproteinase inducer), also called CD147, basigin or M6 in the human, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs). In our study, we investigated expression of EMMPRIN in human normal brain and gliomas, since mouse basigin and chicken HT7, the species homologues of human EMMPRIN, are associated with neuronal interactions and normal blood-brain barrier function, respectively. EMMPRIN expression was detected in all samples of non-neoplastic brain and glioma tissues examined. However, expression levels of EMMPRIN mRNA and protein were significantly higher in gliomas than in non-neoplastic brain. Moreover, levels of mRNA expression and immunohistochemical staining correlated with tumor progression in gliomas: They were highest in the most malignant form of glioma, glioblastoma multiforme, followed by anaplastic astrocytoma and then low-grade astrocytoma. Also, immunolocalization revealed quite different distributions in non-neoplastic brain and glioma: EMMPRIN was demonstrated only in vascular endothelium in non-neoplastic regions of the brain, whereas it was present in tumor cells but not in proliferating blood vessels in malignant gliomas. These data indicate that an MMP inducer molecule EMMPRIN is differently expressed in human normal brain and gliomas and could be associated with astrocytoma progression. Possible mechanisms whereby glioma cell EMMPRIN could influence tumor progression will be discussed.
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PMID:Expression of emmprin (CD147), a cell surface inducer of matrix metalloproteinases, in normal human brain and gliomas. 1096 35

Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.
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PMID:Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. 1105 Dec 33

Nucleoside diphosphate kinases (Nm23/NDPK) are enzymes functional in cell proliferation, differentiation, development, tumor progression, and metastasis. Nevertheless, no consensus exists about the molecular mechanism by which Nm23/NDPK isoforms exert their role in these processes. We investigated the expression of the rat Nm23-R1/NDPKbeta and Nm23-R2/NDPKalpha isoforms, homologues of the human Nm23-H1/NDPK A and Nm23-H2/NDPK B proteins, respectively, upon cAMP-induced differentiation of rat C6 glioma cells and demonstrated a differential interaction with intermediate filaments. Semiquantitative RT-PCR, immunoblotting, and flow cytometry showed a constitutive expression of both Nm23 isoforms. After induction of differentiation in C6 cells with cAMP analogs or isoproterenol, a dose-dependent 2- and 2.5-fold upregulation of the Nm23-R1 mRNA and protein, respectively, was observed. In contrast, the expression of Nm23-R2 remained unchanged. Localization of both isoforms with confocal laser scanning microscopy demonstrated a punctate reticular staining pattern for both Nm23 isoforms in the cytosol and processes of the cells which was particularly intense in the perinuclear region. In addition, while Nm23-R2 was colocalized and coimmunoprecipitated with vimentin in nondifferentiated cells, both isoforms were associated with GFAP in differentiated cells. The significance of these findings in relation to a possible function of Nm23 isoforms in cell proliferation, differentiation, and tumor-associated mechanisms is discussed.
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PMID:Nucleoside diphosphate kinase beta (Nm23-R1/NDPKbeta) is associated with intermediate filaments and becomes upregulated upon cAMP-induced differentiation of rat C6 glioma. 1108 83

The major goal of this study was to determine if treatment with the newly constructed plasmid vector for tumor necrosis factor-alpha (pGL1-TNF-alpha) could enhance the radiation-induced growth reduction of C6 rat glioma. In addition, two different forms of ionizing radiation (gamma-rays and protons) were utilized. Body and spleen mass, leukocyte blastogenesis, and flow cytometry analysis of cell populations in blood and spleen were performed to detect toxicity, if any, and to identify mechanisms that may correlate with the anti-tumor action of combination therapy. C6 tumor cells were implanted subcutaneously into athymic mice and allowed to become established before treatment initiation. pGL1-TNF-alpha was injected into the implanted tumors, which were then irradiated 16-18 hr later; each modality was administered three times over 8-9 days. The addition of pGL1-TNF-alpha significantly enhanced the anti-tumor effect of radiation (p < 0.05). The effect was more than additive, since pGL1-TNF-alpha alone did not slow tumor progression and radiation alone had only a modest effect. Administration of pGL1-TNF-alpha together with proton radiation resulted in tumor volumes that were 23% smaller than those following pGL1-TNF-alpha + gamma-ray treatment; a similar differential in tumor size was observed in the groups receiving only radiation. Body weights and blood and spleen cell analyses did not reveal treatment-related toxicity. High basal proliferation of blood leukocytes and increased B cell levels in the spleen were associated with pGL1-TNF-alpha + 60Co (gamma-radiation) or proton treatment. Overall, the results suggest that the pGL1-TNF-alpha/radiation combination is effective and safe under the conditions employed. This is the first study to combine gene and proton radiation therapy and to show, under controlled experimental conditions, that proton radiation may have a greater effect against malignant tumors compared to the same physical dose of gamma-radiation.
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PMID:Combination of pGL1-TNF-alpha gene and radiation (proton and gamma-ray) therapy against brain tumor. 1120 48

Pharmacyclics is developing Gd-Tex (gadolinium texaphyrin) as a radiosensitizer for the potential treatment of various cancers including brain metastases and primary brain tumors, pancreatic tumors, lung tumors and pediatric cancers [196711], [348919]. The compound entered phase III pivotal trials for brain metastases in September 1998 [323929]. Phase I clinical trials for the treatment of primary brain tumors and pancreatic cancer have been initiated while several trials in other cancer types are in the planning stages [367716]. In September 1998, Pharmacyclics announced the initiation of a pivotal phase III trial for the treatment of patients with brain metastases. This multicenter trial originally included 30 sites in the US, Canada and Europe, and was expected to enroll 425 patients. The FDA agreed that this trial qualified for Fast Track review if efficacy end-points are met [301265]. By October 2000, nearly all 450 patients in 50 sites had been completed [375959], [387023]. In September 2000, Pharmacyclics and the National Cancer Institute (NCI) initiated two phase I trials of Gd-Tex. The first was to determine the safety of two different dosing regimens of the drug during preoperative radiotherapy after induction chemotherapy in patients with stage IIA non-small cell lung cancer (NSCLC). The second would examine the use of Gd-Tex in combination with stereotactic Gamma Knife radiosurgery in patients with primary brain tumors known as glioblastoma multiforme [381561]. A phase Ib/II trial, for brain metastases, was conducted in America and France, and involved over 100 patients. At the ASCO 1998 meeting, interim tumor response data were presented for 37 patients. The overall tumor response rate (complete plus partial response rate) was 73%. Furthermore, MRI scanning confirmed that Gd-Tex accumulated selectively in tumors [287459]. Full results were announced in October 1998 at the American Society of Therapeutic Radiology and Oncology. Following ten daily injections followed by whole brain radiation, 77.7% of patients demonstrated a tumor response defined as greater than 50% reduction in tumor volume. Gd-Tex was well tolerated, and liver enzyme elevation was the dose-limiting effect, which was reversible. Death due to tumor progression was seen in 15% of the Gd-Tex group as opposed to 35% in the control group [302872]. In November 1999, Pharmacyclics commenced a phase I trial of Gd-Tex injection, sponsored by the NCI, for treating children with intrinsic pontine glioma. The goals of the phase I dose-ranging study were to determine the Gd-Tex dose and administration schedule that can be safely administered with radiation and to evaluate the localization of Gd-Tex in affected tumors using MRI [348035]. In March 1997 the Decision Network of the NCI voted to sponsor additional clinical indications including adult and pediatric brain tumors, as well as cancers involving the lung, head & neck, pancreas and prostrate. Two phase I trials of Gd-Tex for the treatment of primary brain tumors commenced in August 1998 under a CRADA with the NCI [237538], [295592], [348919]. Pharmacyclics is collaborating with the NCI under a CRADA in phase I trials in primary brain tumors and pancreatic tumors [323929], [323952], [346596]. Analysts expected a filing to occur by the end of 1999 or early 2000, with sales in 2001 [303186].
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PMID:Gd-Tex Pharmacyclics Inc. 1124 9

Mutations of the tumor suppressor PTEN, a phosphatase with specificity for 3-phosphorylated inositol phospholipids, accompany progression of brain tumors from benign to the most malignant forms. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of angiogenesis, a process termed the angiogenic switch. Therefore, we tested whether PTEN regulates tumor progression by modulating angiogenesis. U87MG glioma cells stably reconstituted with PTEN cDNA were tested for growth in a nude mouse orthotopic brain tumor model. We observed that the reconstitution of wild-type PTEN had no effect on in vitro proliferation but dramatically decreased tumor growth in vivo and prolonged survival in mice implanted intracranially with these tumor cells. PTEN reconstitution diminished phosphorylation of AKT within the PTEN-reconstituted tumor, induced thrombospondin 1 expression, and suppressed angiogenic activity. These effects were not observed in tumors reconstituted with a lipid phosphatase inactive G129E mutant of PTEN, a result that provides evidence that the lipid phosphatase activity of PTEN regulates the angiogenic response in vivo. These data provide evidence that PTEN regulates tumor-induced angiogenesis and the progression of gliomas to a malignant phenotype via the regulation of phosphoinositide-dependent signals.
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PMID:PTEN controls tumor-induced angiogenesis. 1127 65

Microheterogeneity is a routinely observed neuropathologic characteristic in brain tumor pathology. Although microheterogeneity is readily documented by routine histologic techniques, these techniques only measure tumor status at the time of biopsy or surgery and do not indicate likely tumor progression. A biochemical screening technique calibrated against pathologic standards would greatly assist in predicting tumor progression from its biological activity. Here we demonstrate for the first time that proton magnetic resonance spectroscopy (1H MRS) with high-resolution magic-angle spinning (HRMAS), a technique introduced in 1997, can preserve tissue histopathologic features while producing well-resolved spectra of cellular metabolites in the identical intact tissue specimens. Observed biochemical alterations and tumor histopathologic characteristics can thus be correlated for the same surgical specimen, obviating the problems caused by tumor microheterogeneity. We analyzed multiple specimens of a single human glioblastoma multiforme surgically removed from a 44-year-old patient. Each specimen was first measured with HRMAS 1H MRS to determine tumor metabolites, then evaluated by quantitative histopathology. The concentrations of lactate and mobile lipids measured with HRMAS linearly reflected the percentage of tumor necrosis. Moreover, metabolic ratios of phosphorylcholine to choline correlated linearly with the percentage of the highly cellular malignant glioma. The quantification of tumor metabolic changes with HRMAS 1H MRS, in conjunction with subsequent histopathology of the same tumor specimen, has the potential to further our knowledge of the biochemistry of tumor heterogeneity during development, and thus ultimately to improve our accuracy in diagnosing, characterizing, and evaluating tumor progression.
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PMID:Quantification of microheterogeneity in glioblastoma multiforme with ex vivo high-resolution magic-angle spinning (HRMAS) proton magnetic resonance spectroscopy. 1130 25


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