UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding and overcoming multidrug resistance (MDR) may be a promising strategy to develop more effective pharmacotherapies for malignant gliomas. In the present study, human malignant glioma cell lines (n=12) exhibited heterogeneous mRNA and protein expression and functional activity of the mdr gene-encoded P-glycoprotein (PGP) and MDR-associated protein (MRP). Correlation between mRNA expression, protein levels and functional activity was strong. Inhibition of PGP activity by verapamil or PSC 833 enhanced the cytotoxic effects of vincristine, doxorubicin, teniposide and taxol. Inhibition of MRP activity by indomethacin or probenecid enhanced the cytotoxic effects of vincristine, doxorubicin and teniposide. The human cerebral endothelial cell line, SV-HCEC, exhibited the strongest PGP activity of all cell lines. Five primary human glioblastomas and one anaplastic astrocytoma displayed heterogenous protein levels of PGP and MRP-1 in tumor cells and of PGP in biopsy specimens in vivo, but no functional activity of these proteins upon ex vivo culturing. These data suggest that the glioma cell line-associated MDR-type drug resistance is a result of long-term culturing and that cerebral endothelial, but not glioma cells, may contribute to MDR-type drug resistance of gliomas in vivo.
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PMID:P-glycoprotein and multidrug resistance-associated protein mediate specific patterns of multidrug resistance in malignant glioma cell lines, but not in primary glioma cells. 1465 54

Brain tumors, in general, display a multidrug-resistant phenotype. This study evaluated the immunohistochemical expression and distribution of P-glycoprotein (Pgp), multidrug resistance protein (MRP1), lung resistance protein (LRP) and O6 methylguanine-DNA methyltransferase (MGMT) in low- and high-grade astrocytoma, oligodendroglioma and in different subgroups of meningioma. The results revealed a marked heterogeneity in the expression and distribution among the analyzed tumors. In astrocytoma and oligodendroglioma, Pgp and MRP1 were observed in the capillary endothelium and in scattered tumor cells, whereas LRP occurred only in tumor cells. A pronounced expression of MGMT was found independent of the histopathological grade. An enhanced expression of MRP1 and LRP in astrocytoma and oligodendroglioma were more often evident in older patients (> 50 years). Survival analysis suggested a markedly decreased overall survival for patients suffering from low-grade glioma overexpressing Pgp. In meningioma, a heterogeneous expression of Pgp, MRP1, LRP and MGMT was seen with the most prominent staining localized to the capillary endothelium. Pgp was significantly more often overexpressed (p < 0.05) in transitional compared to meningothelial meningioma. The marked heterogeneity in the expression suggests that analysis of these factors can be of importance in the selection of individualized chemotherapy, regardless of tumor type.
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PMID:Heterogeneity in the expression of markers for drug resistance in brain tumors. 1498 30

Tamoxifen, a non-steroidal anti-estrogen widely used against breast cancer, is also useful for treatment of other malignancies, due to its sensitizing effect on other chemotherapeutic agents and radiation. We have investigated the advantages of combining tamoxifen with one of the commonly used cancer chemotherapeutic drug, etoposide (VP-16) in brain tumor cell lines. While tamoxifen (10 microM) increased etoposide cytotoxicity 8.3-fold in the human glioma cell line (HTB-14), it increased etoposide cytotoxicity 47.5- and 40-fold in two primary cell lines established from pediatric medulloblastoma patients (MCH-BT-31 and MCH-BT-39), respectively. Similarly, in the pediatric ependymoma cell lines (MCH-BT-30 and MCH-BT-52), tamoxifen enhanced etoposide cytotoxicity 6- and 2.68-fold, respectively. CalcuSyn analysis of cytotoxicity data showed that tamoxifen and etoposide combinations were synergistic with combination index values ranging from 0.243 to 0.369 at IC50 level among different pediatric brain tumor cell lines. Tamoxifen is also cytotoxic at higher concentrations (> 20 microM) in brain tumor cells. To understand the mechanism underlying the tamoxifen modulation of etoposide cytotoxicity, we analyzed expression of P-glycoprotein (P-gp), insulin-like growth factor-I receptor (IGF-IR), IGF-I, IGF-II and estrogen receptor as well as protein kinase C (PKC) activity. While P-gp, IGF-IR and IGF-I were not affected, enhanced inhibition of PKC, and IGF-II were observed in brain tumor cells treated with tamoxifen and etoposide combination as compared to cells treated with either drug alone. Tamoxifen at 10 microM when combined with etoposide at 0-100 microM concentrations reduced PKC activity 77% compared to only 58% without tamoxifen. IGF-II expression decreased to 48.6% of the untreated control in the combination treatment as compared to 31.2% for etoposide alone and 26.2% for tamoxifen alone treatments. These results suggest that inhibitory effect of tamoxifen on brain tumor cells manifest through different mechanisms involving inhibition of targets such as PKC and IGF-II.
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PMID:Tamoxifen modulation of etoposide cytotoxicity involves inhibition of protein kinase C activity and insulin-like growth factor II expression in brain tumor cells. 1507 44

Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are two highly selective mu-opiate receptor agonists. We recently demonstrated that EM-1 and EM-2 have a saturable transport system from brain-to-blood in vivo. Since the endothelial cells are the main component of the non-fenestrated microvessels of the blood-brain barrier (BBB), we examined whether these endogenous tetrapeptides have a saturable transport system in cultured cerebral endothelial cells. EM-1 and EM-2 binding and transport were studied in a transwell system in which primary mouse endothelial cells were co-cultured with rat glioma cells. We found that binding of both endomorphins was greater on the basolateral than the apical cell surface. Flux of EM-1 and EM-2 occurred predominantly in the basolateral to apical direction, each showing self-inhibition with an excess of the respective endomorphin. Transport was not influenced by the addition of the P-glycoprotein inhibitor, cyclosporin A. Neither the mu-opiate receptor agonist DAMGO nor the delta-opiate receptor agonist DPDPE had any effect on the transport. Thus, the results show that a saturable transport system for EM-1 and EM-2 occurs at the level of endothelial cells of the BBB, and unlike beta-endorphin and morphine, P-glycoprotein is not needed for the brain-to-blood transport. Cross-inhibition of the transport of each endomorphin by the other suggests a shared transport system that is different from mu- or delta-opiate receptors. As endormorphins are mainly produced in the CNS, the presence of the efflux system at the BBB could play an important role in pain modulation and neuroendocrine control.
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PMID:Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells. 1534 52

Vincristine is an integral part of the "PCV" regimen that is commonly administered to treat primary brain tumors. The efficacy of vincristine as a single agent in these tumors has been poorly studied. This study was designed to determine whether vincristine enters normal rat brain or an intracranially or subcutaneously implanted glioma and to assess the presence of the efflux pump P-glycoprotein (P-gp) on tumor and vascular endothelial cells. The 9L rat gliosarcoma was implanted intracranially and subcutaneously in three Fischer 344 rats. On day 7, [3H]vincristine (50 microCi, 4.8 microg) was injected into the carotid artery, and the animals were euthanized 10 or 20 min later. Quantitative autoradiography revealed that vincristine levels in the liver were 6- to 11-fold greater than in the i.c. tumor, and 15- to 37-fold greater than in normal brain, the reverse of the expected pattern with intraarterial delivery. Vincristine levels in the s.c. tumor were 2-fold higher than levels in the i.c. tumor. P-gp was detected with JSB1 antibody in vascular endothelium of both normal brain and the i.c. tumor, but not in the tumor cells in either location, or in endothelial cells in the s.c. tumor. These results demonstrate that vincristine has negligible penetration of normal rat brain or i.c. 9L glioma despite intra-arterial delivery and the presence of blood-brain barrier dysfunction as demonstrated by Evan's blue. Furthermore, this study suggests that P-gp-mediated efflux from endothelium may explain these findings. The lack of penetration of vincristine into brain tumor and the paucity of single-agent activity studies suggest that vincristine should not be used in the treatment of primary brain tumors.
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PMID:Penetration of intra-arterially administered vincristine in experimental brain tumor. 1549 97

The present study was designed to clarify the involvement of nitric oxide (NO) signaling in the adverse effect of cyclosporine on the blood-brain barrier. Cyclosporine increased the permeability of sodium-fluorescein and the cellular accumulation of rhodamine 123, a substrate of P-glycoprotein, in mouse brain endothelial (MBEC4) cells. This effect was markedly enhanced two- to threefold when MBEC4 cells were cocultured with rat astrocytes or C6 glioma cells. Direct and continuous electrochemical measurement of NO demonstrated that cyclosporine dose-dependently increased histamine- and phenylephrine-evoked NO production in MBEC4 cells and astrocytes, respectively. A NO synthase inhibitor (NG-monomethyl-L-arginine) blocked slightly and markedly cyclosporine-induced impairment of the endothelial barrier in the monolayer and coculture system, respectively. These findings suggest that cyclosporine impairs the brain endothelial barrier function by accelerating NO production in the brain endothelial and astroglial cells. This event may be interpreted as triggering the occurrence of cyclosporine neurotoxicity.
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PMID:Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in cocultures of mouse brain endothelial cells and rat astrocytes. 1555 36

Chemotherapy in glioma is poorly effective: the blood-brain barrier and intrinsic and/or acquired drug resistance of tumor cells could partly explain this lack of major effect. We investigated expression of P-glycoprotein (Pgp), multidrug resistance protein (MRP) 1, MRP3, MRP5 and glutathione-S-transferase pi (GST-pi) in malignant glioma patients. Cytofluorimetric analysis of 48 glioma specimens and 21 primary cultures showed high levels of MRP1, moderate levels of MRP5 and low levels of Pgp, GST-pi and MRP3. Immunohistochemistry (25 glioma specimens) showed expression of GST-pi (66.7% of cases), MRP1 (51.3%), MRP5 (45.8%), Pgp (34.8%) and MRP3 (29.9%) in tumor cells. Moreover, analysis of tumor samples by real time quantitative PCR showed mRNA expression of all investigated genes. Tumor vasculature, analyzed in glioma specimens and in tumor derived endothelial cells, showed expression of all investigated proteins. Non-tumor brain samples (from a patient with arteriovenous malformation and from one with epilepsy), normal human astrocytes and cultured endothelial cells were also analyzed: astrocytes and endothelial cells expressed the highest levels of the investigated proteins, mainly MRP1 and MRP5. No significant differences in proteins expression were detected between primary or recurrent gliomas, suggesting that glioma chemoresistance is mostly intrinsic. Therefore, we detected, for the first time, the presence of MRP3 and MRP5 on glioma specimens--both in tumor and endothelial cells--and we delineated an expression profile of chemoresistance proteins in glioma. The possible association of inhibitors of drug efflux pumps with chemotherapy could be investigated to improve drugs delivery into the tumor and their cytotoxic effects.
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PMID:Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma. 1619 81

In cancer treatment, efficient therapeutic strategies could be impeded by cellular mechanisms such as the multidrug resistance. Recently, drug-loaded nanoparticles have been reported to be useful, since they allow entering the cancer cell and act as an intracellular anti-cancer drug reservoir. A new approach is proposed here by the use of lipid nanocapsules (LNC) which were hypothesized to reverse multidrug resistance additionally by their P-glycoprotein (P-gp) inhibiting surfactant. LNC (mean diameter 25 to 100 nm) were loaded with etoposide, tested for the drug release and their efficiency to reduce cell growth in cell culture for C6, F98, and 9L glioma cell lines. Sustained etoposide release can be provided over a period of 1 week (t10%: 1.4+/-0.1h; t50%: 15.9+/-2.8h). The P-gp inhibiting activity in-vitro was found to be independent from the LNC size. In cell culture, an internalization of LNC was observed in all glioma cell types. Etoposide LNC showed a generally higher efficiency than the drug solution while blank LNC were found to be less inhibitory than the pure drug at equivalent concentrations (IC50: C6: etoposide: 25.2 microM; LNC: 2.6-8.9 microM, F98: etoposide: 46.5 microM; LNC: 1.4-14.7 microM, 9L: etoposide: 58.2 microM; LNC: 4.4-12.7 microM). This effect was found to be particle size dependent within a range of an 8- (C6) to 33-fold (F98) increased cytotoxicity for smallest particles. When cells were incubated with etoposide solution in the presence of blank LNC, a slight growth inhibition was observed, however, distinctly lower than the drug-trapping particles. Moreover, cell toxicity on astrocytes was similar for etoposide LNC and etoposide solution. The mechanism of action of etoposide LNC was proposed to be a cell uptake followed by a sustained drug release from the LNC in combination with an intracellular P-gp inhibition ensuring a higher anticancer drug concentration inside the cancer cells.
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PMID:Etoposide nanocarriers suppress glioma cell growth by intracellular drug delivery and simultaneous P-glycoprotein inhibition. 1771 50

The cytotoxicity of doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles (Dox-PBCA-NP) was investigated in the rat glioma cell lines GS-9L, F-98 and RG-2. MTT and LDH assays were used as cytotoxic assays. In general, the cytotoxicity of nanoparticle-bound doxorubicin (Dox) was enhanced compared to the free drug in solution. However, responses of the cell lines towards the drug effects were different. In the case of free Dox in solution, this difference correlated with different intracellular concentrations of Dox, which in turn, depended on the level of P-glycoprotein (P-gp) expression in these cell lines. Accordingly, the 9L gliosarcoma (GS-9L) cells, which appeared to be most resistant towards Dox, were characterized by the highest P-gp expression.Additionally, the influence of surfactants on the cytotoxic effect was investigated at different Dox concentrations. It was shown that the presence of polysorbate 80 (Tween 80) in the nanoparticle formulation significantly enhanced the cytotoxicity, whereas poloxamer 188 (Pluronic F68) and poloxamine 908 (Tetronic 908) had a negligible influence.
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PMID:Cytotoxicity of doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles in rat glioma cell lines using different assays. 1709 Mar 97

The authors have previously shown that medroxyprogesterone acetate (MPA) inhibits growth and increases drug sensitivity in C6 glioma with myeloid bodies. Myeloid bodies can occur in cells either due to robust toxicity with mitochondrial membrane disruption or due to milder events such as seen in lysosomal-phospholipidosis. Exact patterns of myelinosis accompanying to MPA chemo-sensitization is important, because uncoupling of nuclear versus mitochondrial toxicity of anti-neoplastics by MPA would lead to safer employment of glioma chemotherapy with reduced neurotoxicity. By monitoring and comparing cell kinetics with fine structural features of cell death, the authors estimated subcellular effects accompanying growth-inhibitory drug actions in C6 glioma. The analysis revealed that MPA induced mainly lysosomal phospholipidosis, while inhibiting clonogenicity alone and augmenting procarbazine efficacy. It induced apoptosis in combination with cisplatin. It reduced mitochondrial-damage-based early cytotoxicity of methotrexate, yet it did not hinder its anti-clonogenic efficacy. Progesterone analogues - similar to antidepressants - inhibit cholesterol esterification, and this efficacy relates with their P-glycoprotein inhibition. Reducing esterification and plasma-membrane localization of cholesterol may lead MPA induction of lysosomal phospholipidosis, growth indolency, and drug sensitization in glioma.
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PMID:Medroxyprogesterone acetate induces c6 glioma chemosensitization via antidepressant-like lysosomal phospholipidosis/myelinosis in vitro. 1772 57

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