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)

Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethy-3-nitrosourea (ACNU) for 2 to 4 hr resulted in a 2- to 3-fold increase in steady-state levels of multidrug resistance-associated protein (MRP) and gamma-glutamylcysteine synthetase (gamma-GCS) mRNA. Nuclear run-on assays revealed a less than 0.5-fold increase in transcription rates of these genes under the same treatment conditions, suggesting that posttranscriptional regulation plays an important role for the increased mRNA levels. In the absence of ACNU, rates of MRP and gamma-GCS mRNA degradation were similar in A172 cells as determined by incubating cells with the RNase inhibitor, Actinomycin D. ACNU treatments resulted in increased MRP mRNA stability. Induction of MRP and gamma-GCS mRNA by ACNU apparently did not require de novo protein synthesis as determined by the use of protein synthesis inhibitor cycloheximide (CHX). However, CHX alone could induce accumulation of gamma-GCS mRNA, also by posttranscriptional mechanism. Taken together, these results demonstrate that (i) posttranscriptional regulation is primarily involved in the induction of MRP and gamma-GCS expression by ACNU and CHX in human glioma cells; and (ii) despite the fact that these two genes have been reported to be frequently co-expressed, their responses to the treatments of RNA and protein synthesis inhibitors are not the same.
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PMID:Posttranscriptional regulation of MRP/GS-X pump and gamma-glutamylcysteine synthetase expression by 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea and by cycloheximide in human glioma cells. 934 68

Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), an alkylating antitumor agent the primary target of which has been thought to be DNA, resulted in elevated expression of mRNA for multidrug resistance-associated protein (MRP) within the first 2 h and then a decrease in expression 24 h after the treatment. Western blot analyses revealed that levels of MRP in these ACNU-treated cells paralleled mRNA levels. Membrane vesicles prepared from ACNU-treated cells also displayed elevated transport activities for leukotriene C4, a known substrate for MRP. Gamma-glutamylcysteine synthetase (gamma-GCS) mRNA expression was coinduced with MRP by ACNU. Because gamma-GCS is the rate-limiting enzyme involved in the de novo biosynthesis of glutathione, increases in glutathione were also transiently induced by ACNU. These results demonstrate for the first time that the expression of functional MRP and gamma-GCS can be transiently coinduced by ACNU. Multiple short exposures (1 h) of ACNU following a long duration (1 week) of drug-free conditions resulted in the development of an ACNU-resistant population (designated A172R) that overexpressed MRP/gamma-GCS mRNA and had elevated transport activities for leukotriene C4. A172R exhibited cross-resistance to the antitumor drug doxorubicin and heavy metal sodium arsenate but not to cisplatin. Our results also demonstrate that intermittent treatments of human glioma cells with ACNU can lead to the development of MRP-related multidrug resistance. These results, taken together, reveal a possible new mechanism of the development of drug resistance for the antitumor nitrosoureas.
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PMID:Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells. 939 52

Here, we report that nonsteroidal anti-inflammatory drugs (NSAID) enhance the cytotoxic effects of doxorubicin and vincristine in T98G human malignant glioma cells. The cytotoxicity of BCNU, cisplatin, VM26, camptothecin, and cytarabine is unaffected by NSAID. No free radical formation is induced by doxorubicin or vincristine in the absence or presence of NSAID. Doxorubicin and vincristine cytotoxicity in the absence or presence of NSAID are unaffected by free radical scavengers. Functional inhibitors of phospholipase A2 (PLA2), such as dexamethasone and quinacrine, do not mimick the effects of NSAID. T98G cells, but not LN-18, LN-229, LN-308, or A172 glioma cells, express cyclooxygenase (COX-1) and NSAID do not modulate drug cytotoxicity in the other cell lines, except T98G. Thus, augmentation of doxorubicin and vincristine cytotoxicity by NSAID correlates with COX-1 expression. However, ectopic expression of COX-1 in LN-229 cells does not induce the phenotype of T98G cells, indicating that COX-1 inhibition does not mediate the effects of NSAID on drug cytotoxicity. In contrast, a multidrug resistance (MDR) phenotype due to expression of the multidrug resistance-associated protein (MRP) is most prominent in T98G cells and is amenable to modulation by indomethacin, suggesting that inhibition of MRP is at least in partly responsible for the potentiation of doxorubicin and vincristine cytotoxicity by NSAID.
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PMID:Selective potentiation of drug cytotoxicity by NSAID in human glioma cells: the role of COX-1 and MRP. 1036 64

Cocultures of human umbilical vein endothelial cells (ECV304) and rat glioma cells (C6) from two commercial sources, American Type Culture Collection and European Collection of Animal Cell Cultures, were evaluated as an in vitro model for the blood-brain barrier. Monolayers of endothelial cells grown in the presence or absence of glial cells were examined for transendothelial electrical resistance, sucrose permeability, morphology, multidrug resistance-associated protein expression, and P-glycoprotein expression and function. Coculture of glial cells with endothelial cells increased electrical resistance and decreased sucrose permeability across European endothelial cell monolayers, but had no effect on American endothelial cells. Coculture of European glial cells with endothelial cells caused cell flattening and decreased cell stacking with both European and American endothelial cells. No P-glycoprotein or multidrug resistance-associated protein was immunodetected in endothelial cells grown in glial cell-conditioned medium. Functional P-glycoprotein was demonstrated in American endothelial cells selected in vinblastine-containing medium over eight passages, but these cells did not form a tight endothelium. In conclusion, while European glial cells confer blood-brain barrier-like morphology and barrier integrity to European endothelial cells in coculture, the European endothelial-glial cell coculture model does not express P-glycoprotein, normally found at the blood-brain barrier. Further, the response of endothelial cells to glial factors was dependent on cell source, implying heterogeneity among cell populations. On the basis of these observations, the umbilical vein endothelial cell-glial cell coculture model does not appear to be a viable model for predicting blood-brain barrier penetration of drug molecules.
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PMID:Evaluation of an in vitro coculture model for the blood-brain barrier: comparison of human umbilical vein endothelial cells (ECV304) and rat glioma cells (C6) from two commercial sources. 1061 67

Drug resistance is a major clinical problem in the chemotherapy of human gliomas. The multidrug resistance-associated protein (MRP), a membrane transporter related to non-P-glycoprotein multidrug resistance, is overexpressed in some drug-selected cancer cell lines. To investigate whether MRP is involved in the intrinsic drug resistance of human gliomas, surgical specimens of 20 gliomas (11 glioblastomas, 6 anaplastic astrocytomas, and 3 astrocytomas), 3 normal brain specimens, and 4 glioma cell lines (U87MG, U251MG, U373MG, and T98G) were analyzed. The expression of MRP was studied by RT-PCR and immunohistochemistry in the surgical specimens. The MRP expression levels in the cell lines were assessed by the quantitative RT-PCR and Western blot analyses. Sensitivity to adriamycin (ADM), etoposide (VP-16), cisplatin (CDDP), and 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), were determined by MTT assay, and antisense treatment was evaluated in the cell lines. The expression of MRP was detected in 9 of 11 glioblastomas and 3 of 6 anaplastic astrocytomas. The quantitative analyses of the cell lines revealed that the MRP mRNA and protein levels were increased 4.5-fold in the T98G cells as compared to U87MG. T98G cells showed the highest resistance to all drugs. Western blot analysis revealed that treatment with the antisense oligonucleotide reduced the level of MRP expression to 25% of the sense oligonucleotide treatment in T98G cells. The sensitivity to ADM, VP-16 and CDDP was significantly increased in the antisense-treated cells as compared with the sense-treated cells. These results suggest that the MRP expression may be related to the intrinsic multidrug resistance in human gliomas.
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PMID:Expression of multidrug resistance-associated protein (MRP) in human gliomas. 1120 6

To clarify the influence of biochemotherapy on the progression of astrocytic tumors, the expression of O6-methylguanine DNA-methyltransferase (MGMT) mRNA, as well as of other drug-resistance- and drug-sensitivity-related genes such as multidrug resistance gene 1, multidrug resistance-associated protein, glutathione S-transferase-pi, DNA topoisomerase II, and interferon receptor mRNA, and the interferon regulatory factor (IRF)-1 and -2 ratios in gliomas were investigated by quantitative reverse transcription-polymerase chain reaction (RT-PCR). The mean MGMT/beta2-microglobulin (beta2-MG) ratio for 130 neuroepithelial tumors was 8.2 +/- 17.8. The mean ratio of 45 glioblastomas was significantly higher than that for the other 85 tumors. In contrast, the mean of 26 low-grade gliomas was significantly lower than that of other tumors. The mean IRF-1/IRF-2 ratio of 16 other brain tumors that mainly consisted of medulloblastomas was significantly greater than that of the other 114 tumors. Almost no significant differences were observed between primary and recurrent tumors in the expression of any gene, and before and after therapy with corresponding drugs. The mean MGMT/beta2-MG ratio in primary glioblastomas was significantly higher than that in secondary tumors. These findings suggest that native drug resistance is more important than acquired resistance when glioma therapy is considered.
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PMID:Drug-resistance gene expression and progression of astrocytic tumors. 1190 69

We examined the effects of suppressing multidrug resistance-associated protein 1 (MRP1) gene expression in a human glioma cell line U87MG. Hammerhead ribozymes, designed to cleave MRP1 mRNA (alphaMRP1-Rz), were transfected into the U87MG cells. The U87MG/alphaMRP1-Rz cells were significantly sensitive to nitrosourea (ACNU) and doxorubicin (DOX) compared with the U87MG cells (p<0.01 and p<0.05, respectively, unpaired t-test). There was no significant difference in the expression of other human genes between the U87MG/alphaMRP1-Rz and controls by cDNA array. The hammerhead ribozyme-mediated specific suppression of MRP1 was sufficient to reverse the resistance of ACNU and DOX in the human glioma cell line.
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PMID:Reversal of drug resistance mediated by hammerhead ribozyme against multidrug resistance-associated protein 1 in a human glioma cell line. 1263 74

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

The emergence of multidrug resistance (MDR) is a major obstacle to successful chemotherapy of malignant glioma tumors. Overexpression of the multidrug resistance-associated protein isoform 1 (MRP1), associated with a high level of intracellular glutathione (GSH), is a well-characterized mechanism of MDR in glioma cells. Previously, we have investigated the role of GSH and MRP1 in the accumulation of two radiopharmaceuticals classically used in nuclear medicine: (99m)Tc-sestamibi (MIBI) and (99m)Tc-tetrofosmin (TFOS), in a model of glioma cell lines. Although the involvement of GSH in MRP1-mediated transport of the two radiopharmaceuticals has been demonstrated, the exact transport mechanisms involving phase II (conjugation) and phase III (efflux) detoxification of these lipophilic cations has not been fully elucidated. To clarify the difference of release kinetics observed between MIBI and TFOS, we have studied the efficiency of formation of monogluthationyl conjugates mediated by glutathione S-transferses (GSTs). Our results clearly demonstrate that, in our model, the main efflux mechanism for radiopharmaceuticals is on monoglutathionyl-conjugates of MIBI (MIBI-SG) and TFOS (TFOS-SG). These mechanisms involving MRP1, and the phase II of detoxification is not efficient for TFOS in resistant glioma cells. A relatively slower catalytic efficiency of formation of TFOS-SG conjugate (0.006%.s(-1)) prevents its expulsion, contrary to MIBI (0.133%.s(-1)), suggesting that TFOS should be interesting in the detection and management of patients with high-grade glioma.
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PMID:Study of monoglutathionyl conjugates TC-99M-sestamibi and TC-99M-tetrofosmin transport mediated by the multidrug resistance-associated protein isoform 1 in glioma cells. 1598 70

This study is to explore and compare the features of the cells and cancer stem-like cells (CSCs) isolated from both glioblastoma and astrocytoma on expression of anti-apoptotic and multidrug resistance-associated protein (MRP) genes. As a result, the mRNA expression of livin, livinalpha and MRP1 was up-regulated in human CSCs from 2 times to 85 times, but the gene expression of MRP3 was down-regulated from 0.09 times to 0.5 times. After just differentiation the mRNA expression of livin, livinalpha and MRP3 was up-regulated from 9 times to 64 times, but the mRNA expression of MRP1 was down-regulated from 0.01 times to 0.03 times. It is a rare report that glioma stem-like cells can be induced successfully from a grade 2-3 astrocytoma tissue. The properties of glioblastoma and astrocytoma stem-like cells on anti-apoptotic and MRP genes are: anti-apoptotic gene livin and survivin are elevated in CSCs but are the most increased in just differentiated CSCs; MRP1 gene is significantly increased and MRP3 is decreased in CSCs, but when differentiating the MRP3 gene starts a remarkable increase in CSCs; the expression of anti-apoptotic and MRP genes shows no differences between the CSCs isolated from glioblastoma and astrocytoma tissues.
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PMID:Comparison between cells and cancer stem-like cells isolated from glioblastoma and astrocytoma on expression of anti-apoptotic and multidrug resistance-associated protein genes. 1846 87


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