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)

Glioblastomas are particularly resistant to classical antitumor treatments. Retinoids, which proved effective in the treatment of promyelocytic leukemia, have been used for clinical assays on glioma tumors with only moderate effects; however in some cases they were active in combination with another therapy. These observations prompted us to analyse the efficacy of combining retinoic acid (RA) with a cytokine on a clonal human glioma cell line. On GL-15 cells, RA and tumor necrosis factor alpha (TNFalpha) both reduced the glial fibrillary acidic protein level and DNA synthesis and induced apoptotic pathways, but they were significantly more effective when used together. The up-regulation of the p55 TNF receptors observed during RA exposure might explain this cooperative effect.
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PMID:Effects of retinoic acid and tumor necrosis factor alpha on GL-15 glioblastoma cells. 1067 92

The neuroblastoma x glioma NG108-15 hybrid cell line, a widely used model for the study of neuronal differentiation, contains a variety of gangliosides including GM1 and its sialosylated derivative, GD1a. To investigate the role of these a-series gangliotetraose gangliosides in neuritogenesis, we have obtained a mutated subclone of NG108-15 that is deficient in that family of gangliosides. NG108-15 cells were grown in the presence of cholera toxin, which killed the large majority of cells, and from the cholera-resistant survivors we isolated a clone, NG-CR72, that lacks GM1 and GD1a in the plasma and nuclear membranes. GM2 concentration was significantly higher in the plasma membrane. Enzyme assay indicated deficiency of UDP-Gal:GM2 galactosyltransferase (GM1 synthase), which was confirmed by incorporation studies with [3H]sphingosine. These cells resembled wild-type NG108-15 in extending dendritic processes in response to dendritogenic agents (retinoic acid, dibutyryl cAMP) but responded aberrantly to axonogenic stimuli (KCl, ionomycin) by extending unstable neurites that showed the cytoskeletal staining characteristic of dendrites. Moreover, mutant cells treated with the Ca2+ elevating axonogenic agents underwent apoptosis over time, attributed to dysfunction of Ca2+ regulatory mechanisms normally mediated by GM1. Such agents caused dramatic and sustained elevation of intracellular Ca2+ in mutant cells, in contrast to modest and temporary elevation in wild-type cells. Exogenous GM1, inserted into the plasma membrane, had no discernable protective effect on NG-CR72 cells whereas LIGA-20, a membrane-permeant derivative of GM1 that entered both plasma and nuclear membranes, blocked apoptosis, permitted extension of stable neurites, and attenuated the abnormal elevation of intracellular Ca2+.
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PMID:Mutant NG108-15 cells (NG-CR72) deficient in GM1 synthase respond aberrantly to axonogenic stimuli and are vulnerable to calcium-induced apoptosis: they are rescued with LIGA-20. 1115 39

Retinoids participate in the onset of differentiation, apoptosis and the inhibition of growth in a wide variety of normal and cancerous cells. Several recent reports have shown that hepatocyte growth factor (HGF), and its receptor, c-Met, are expressed at abnormally high levels in various human malignant gliomas and exert a strong proliferative action in an autocrine fashion. These results, consequently, imply that HGF and its receptor may represent a major contributor to the progression of such malignancies. Since astrocytomas are the most frequently occurring glioma, we have shown here that U87 cells - a well-established, human astrocytoma cell line - express both HGF and c-Met, thereby providing a suitable astrocytic tumor model for studying the potential role of HGF, functioning in an autocrine mode, in astrocytic tumorigenesis. Furthermore, we demonstrated the expression of the retinoic acid receptor (RAR) isoforms, RARalpha, -beta and -gamma, as well as the retinoid x-receptor (RxR) isoforms, RxRalpha and -beta, by RT-PCR and western blot analysis in these cells. Since ligands of the RARs and RxRs are known to exert growth inhibitory effects on various tumor cells which include some astrocytomas, we speculated that such effect of retinoids might be mediated via inhibition of HGF secretion in human astrocytoma cells. Indeed, we have shown that the RAR agonists, all-trans retinoic acid (ATRA) and (E)-4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid (TTNPB), inhibited HGF secretion with half maximal inhibition occurring at 3.0 microM and 15 nM, respectively, as did the RxR agonists, 9-cis- and 13-cis retinoic acid (9cRA and 13cRA, respectively), which exerted half-maximal inhibitory effects at 40 and 25 nM, respectively. These actions of the RAR and RxR agonists appear to be exerted at the transcriptional level as assessed by Northern blot analysis. Taken together, our results show for the first time that retinoids, acting via the RAR and RxRs, significantly inhibit both the secretion and expression of HGF, thereby interrupting a potentially highly tumorigenic autocrine loop in astrocytoma cells.
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PMID:Agonists of the retinoic acid- and retinoid X-receptors inhibit hepatocyte growth factor secretion and expression in U87 human astrocytoma cells. 1122 64

Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.
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PMID:Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma. 1130 15

Aquaporin-4 (AQP4), a mercury-insensitive water channel protein, is abundant in the central nervous system and is localized in astrocytes and ependymal cells. AQP4 is speculated to maintain the homeostasis of intracellular and extracellular water in the brain, but little is known about the mechanism of induction of its expression. To investigate the expressional regulation of AQP4, we analyzed changes in its expression during chemically induced differentiation of embryonal carcinoma cells (P19) to neuronal and astrocytic cells, and during the cell cycle of glioma cells. After exposure to retinoic acid for 4 days AQP4 mRNA expression started at the initiation of astrocytic differentiation of P19 cells at 6 days, and increased markedly by 21 days. AQP4 expression was parallel to that of GFAP, a marker intermediate filament of astrocytes. In glioma cell lines, AQP4 mRNA was not detected in the growing phase, but was induced when the cell cycle was arrested at G0/G1 by transient expression of p21. Although quiescent astrocytes in the G0/G1-phase cultured under the serum-free condition exhibited a high expression of AQP4, serum supplement moved them to the S-phase and markedly decreased the AQP expression. These results suggest that AQP4 expression may be induced not only at the initiation of astrocytic differentiation of neural stem cells, but also at the G0/G1-phase during the cell cycle of astrocytes.
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PMID:Regulation of aquaporin-4 expression in astrocytes. 1131 79

The molecular mechanisms underlying the heterogeneous effects of retinoic acid (RA) treatment on malignant glioma cells remain poorly understood. In this study, we present the first evidence of a functional role of the signal transduction factors (STATs) in RA-induced proliferation, in a human glioblastoma GL-15 cell line. We first observed that STAT-3 was constitutively activated and present in the GL-15 cell nuclei. We then showed that at low doses (0.01-1 microM) RA increased both the proliferation rate of GL-15 cells and the phosphotyrosine (PY) activation of STAT-3. This RA effect involved transcriptional processes and the transactivation of RA target genes, including RA receptors isoforms RARalpha2, -beta2, and -gamma2. At higher concentrations, however, RA (5-10 microM) inhibits GL-15 proliferation, induces apoptosis, and fails to activate STAT-3. An inhibitory effect on GL-15 proliferation was also observed with the synthetic retinoids CD-437 and CD-2325, two structurally related RARgamma agonists, which also fail to activate STAT-3. In addition, the phorbol ester PMA, an inducer of GL-15 differentiation, and staurosporine, a broad inhibitor of protein kinases, abrogate the stimulatory effects of RA at low concentrations. Together these observations suggest that, in GL-15 cells, activation of STAT-3 and cell proliferation share common mechanisms and that STAT transcription factors may be involved in a switch between proliferation, differentiation, and apoptosis. The proliferating effect observed at low doses of RA may be related to the failures in RA efficiency observed in clinical assays in relapsing malignant gliomas. Combining specific inhibitors of tyrosine kinases with RA might optimize the clinical outcome.
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PMID:Retinoic acid increases proliferation rate of GL-15 glioma cells, involving activation of STAT-3 transcription factor. 1189 79

Despite tremendous advances in brain tumor molecular biology and several emerging novel therapies, multimodality therapy that includes surgery, radiation therapy (RT), and chemotherapy is still the cornerstone of high-grade glioma treatment. The first step in high-grade glioma therapy is surgery and a maximal resection should be attempted to reduce the tumor burden before initiation of other adjuvant therapies. External beam radiation therapy (EBRT) generally follows surgery, using conventional dosage, and fractionation, and ideally a three-dimensional conformal technique. Stereotactic radiosurgery (SRS) to maximize cytoreduction may be used in selected cases. Because no curative chemotherapy exists for high-grade glioma, we always consider an investigational agent either before or concurrently with RT. However, the use of a standard cytotoxic agent, such as temozolomide alone or combined with 13-cis-retinoic acid also is a rational choice particularly for patients with relatively good prognostic factors for whom an investigational agent would not be available. The management of anaplastic oligodendroglioma does not differ significantly from other high-grade gliomas in terms of surgery, RT, or investigational or protocol agent; however, these tumors appear to respond to chemotherapy that includes a combination of procarbazine, CCNU, and vincristine (PCV) [1**]. The vincristine provides more toxicity than benefit and it is our practice to only use a combination of procarbazine and CCNU (PC). A single agent, such as temozolomide is an increasingly used and rational choice for anaplastic oligodendroglioma. It is our belief that early, aggressive multimodality treatment still provides the best chance for long-term control of high-grade gliomas, particularly in patients with good prognostic factors. However, despite best therapy and state-of-the-art technology, most patients with high-grade glioma will experience progression or recurrence and will require either a change in the ongoing therapeutic strategy or additional treatment. Better therapies are necessary and progress will only be made through investigation of promising agents in well-designed clinical trials.
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PMID:Adults with newly diagnosed high-grade gliomas. 1205 96

Melanoma-inhibiting activity/cartilage-derived retinoic acid-sensitive protein, a 11 kDa protein, is mainly expressed in cartilage during embryogenesis, and is related to invasion, metastasis, and immunomodulation of melanoma and glioma cells in vivo and in vitro. Here, we describe an alternative splice product of this gene termed melanoma-inhibiting activity (splice), lacking exon 2 of the original protein. A predicted frameshift by alternate splicing results in a unique C-terminal portion of the protein. Consistent with this, a protein migrating at the predicted molecular weight of the splice form (3.5 kDa) was detected using an N-terminal specific antibody. This band was undetectable when using a C-terminal specific antibody. In addition, we describe the expression pattern of melanoma-inhibiting activity (splice) in different human tumors. Expression was shown in tissue samples of five of six primary melanomas, 11 of 12 primary sites of metastatic melanomas, 10 of 10 systemic metastases of melanomas, four of four central nervous system metastases of melanomas, six of eight primary melanoma cultures, and five of five melanoma cell lines. Only a faint signal was obtained in tissue samples of five of six naevi. Interestingly, seven of eight nonmelanocytic tissue samples and five of seven glioma cell lines showed weak expression of melanoma-inhibiting activity (splice). Approaching first functional aspects, reverse transcriptase-polymerase chain reaction showed weak expression of melanoma-inhibiting activity (splice) in relation to melanoma-inhibiting activity in nonmelanocytic and strong expression in melanocytic cells. Staining with a specific anti-serum raised against a synthetic peptide resembling the amino acid sequence of melanoma-inhibiting activity (splice) showed a more nuclear staining pattern in comparison with melanoma-inhibiting activity. Furthermore, incubation of melanoma and glioma cell cultures with transforming growth factor-beta2 showed inverse regulation of the mRNA of melanoma-inhibiting activity and melanoma-inhibiting activity (splice), both suggesting also a different function within the physiologic role of this unique family of proteins. Melanoma-inhibiting activity (splice) has no homology to any other known protein so far. Whereas the biologic function of melanoma-inhibiting activity (splice) is not clear yet, it might provide a relevant diagnostic and therapeutic tool for malignant melanomas.
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PMID:Cloning and characterization of the expression pattern of a novel splice product MIA (splice) of malignant melanoma-derived growth-inhibiting activity (MIA/CD-RAP) [corrected]. 1223 Apr 96

Since malignant glioma displays moderate resistance to conventional therapy, a new treatment modality is needed to improve the outcome of patients with these tumors. In this study, we examined whether combination stimulation with interferon alpha (IFN-alpha) and retinoic acid (RA) affected proliferation of the glioblastoma cell line GB 12 in vitro. Stimulation with IFN-alpha alone inhibited the GB 12 cell proliferation in a dose/time-dependent fashion, as assessed by WST-1 assay and uptake of 3H-thymidine, while RA limited it only slightly. The anti-proliferative action of IFN-alpha against glioblastoma cells was enhanced by the addition of RA. The IFN-alpha/RA combination also induced apoptosis in a substantial portion of the cells, compared with either reagent alone. Bcl-2 family proteins, regulating apoptosis, were altered by these stimuli: Bcl-2 was down-regulated, while Bax-alpha was up-regulated, especially by the combination. These findings suggest that the IFN-alpha/RA combination would synergistically affect glioblastoma cell growth, probably through apoptosis induction as well as a decreased cellular DNA synthesis.
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PMID:Combined stimulation with interferon alpha and retinoic acid synergistically inhibits proliferation of the glioblastoma cell line GB12. 1239 8

Confluent cell monolayers of brain capillary endothelial cells (BCEC) are used widely as an in vitro cell culture model of the blood-brain barrier. The present study describes the influence of cell-culture conditions on tight junctions, filamentous-actin cytoskeleton, and expression of ATP-binding cassette (ABC) transporters in primary cell cultures of porcine BCEC. Astrocyte as well as C6 glioma-conditioned cell culture medium was used in combination with retinoic acid, dexamethasone, cyclic adenosine monophosphate (cAMP) analogs, or 1,25-dihydroxyvitamin D3. It was shown that C6-conditioned medium led to a reorganization of filamentous actin and to an improved staining of zonula occludens-associated protein-1 (ZO-1). Further optimization of these culture conditions was achieved with cAMP analogs and dexamethasone. Retinoic acid, as well as 1,25-dihydroxyvitamin D3, did not improve cellular tight junctions as judged by filamentous actin, ZO-1 rearrangement, and transcellular electrical resistance (TER) measurements. However, these morphological changes did not influence the paracellular permeability of the extracellular marker sucrose. Expression of ABC transporters such as P-glycoprotein, multidrug resistance-associated protein-1(MRP1), and MRP2 were compared by measuring messenger RNA (mRNA) levels in whole-brain tissue, isolated brain capillaries, and cultured cells. In freshly isolated BCEC, mRNA levels of MRP2 and P-glycoprotein dropped by two- to sevenfold, respectively, whereas MRP1 mRNA levels were slightly increased. During cell culture, mRNA levels of MRP1 and MRP2 decreased by up to fivefold, while P-glycoprotein levels remained constant. These results were unaltered by different cell-culture conditions. In conclusion, the present study suggests that paracellular permeability, as well as mRNA expression of the studied ABC transporters in primary cultures, of porcine BCEC are insensitive toward changes in cell-culture conditions.
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PMID:Modulation of transendothelial permeability and expression of ATP-binding cassette transporters in cultured brain capillary endothelial cells by astrocytic factors and cell-culture conditions. 1461 Jun 30


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