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 studied the cytotoxicity of five polyoxoanions on two human malignant glioma cell lines (T98G and 86HG39), a rat glioma cell line (C6) and a human fibroblast cell line (NIH-3T3) using MTT tests to measure the drug concentration killing 50% of the cells (LC50). Cisplatin was used as a reference agent. Cisplatin had the highest efficacy in three of the four cell lines. Only in T98G cells, one of the components (POA5) had a lower LC50 value (1.3 x 10(-6) mol/l) than cisplatin (2.5 x 10(-6)). POA5 was also the most cytotoxic polyoxoanion when the LC50 values of all four cell lines were averaged (6.6 x10(-6)). Average LC50 values of the other compounds were 10.9, 12.6, 19.0 and 19.2 x 10(-6) mol/l in POA1, POA2, POA3 and POA4, respectively. When the benign fibroblasts were used to calculate a therapeutic index as LC50 in fibroblasts divided by LC50 in glioma cells, POA5 was superior to cisplatin. These results indicate that polyoxoanions are cytotoxic for malignant glioma cells and that the most promising compound investigated here was POA5.
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PMID:Polyoxoanions are cytotoxic to malignant glioma cells. 984 Jul 27

We have previously demonstrated that treatment of wild-type (wt) T98G malignant glioma cells with Cisplatin (CDDP) led to a resistant phenotype. It has been demonstrated that interleukin 1 (IL-1) potentiates the cytotoxic effect of CDDP and that IL-6 decreases cytotoxicity by inhibition of apoptosis in cancer cells. Here we examined the influence of IL-1 and IL-6 on the sensitivity of resistant and wt T98G cells. Using semi-quantitative PCR reactions in three independent experiments, resistant glioma cells revealed a decreased IL-1alpha (50.3+/-7.2), IL-1beta (56.0+/-4.0) and IL-6 (44. 3+/-18.2) mRNA content compared to wt cells (100%;P<0.05). Resistant and wt cells were positive for the receptors IL-1RI and IL-6R (PCR). To investigate whether IL-1alpha, IL-1beta or IL-6 changes the sensitivity of the resistant and wt cells towards CDDP, cells were incubated up to 7 days with 10(-5) M CDDP and with different concentrations (0, 0.01, 0.1, 1 ng/ml) of cytokine. Sensitivity was tested in a colorimetric assay (MTT). IL-6 did not influence the sensitivity towards CDDP of either wt or resistant cells, while IL-1alpha and IL-1beta enhanced sensitivity of resistant cells to CDDP. These data suggest that autocrine IL-1 production is involved in the mechanisms of resistance in T98G cells.
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PMID:In vitro modulation of cisplatin resistance by cytokines. 1047 5

Efficacy of chemotherapy is limited in numerous tumors by specific cellular mechanisms that inactivate cytotoxic antitumoral drugs, such as ATP-dependent drug efflux and/or drug detoxification by glutathione. In reducing ATP pools and/or glutathione synthesis, it might be possible to enhance the efficacy of drugs affected by such resistance mechanisms. Reduction of the ATP pool and glutathione content is achievable in cancer cells by depleting the exogenous methionine (Met) supply and ethionine. Thus, the rationale for the present study was to use Met depletion to decrease the ATP and glutathione pools so as to sensitize tumors refractory to cytotoxic anticancer drugs. Met depletion was achieved by feeding mice a methionine-free diet supplemented with homocysteine. The effects of Met depletion combined with ethionine and/or chemotherapeutic agents were studied using human solid cancers xenografted into nude mice. TC71-MA (a colon cancer) SCLC6 (a small cell lung cancer), and SNB19 (a glioma) were found to be refractory to cisplatin, doxorubicin, and carmustine, respectively. These three drugs are used to treat such tumors and are dependent for their activity on the lack of cellular ATP- or glutathione-dependent mechanisms of resistance. TC71-MA, SCLC6, and SNB19 were Met dependent because their proliferation in vitro and growth in vivo were reduced by Met depletion. Cisplatin was inactive in the treatment of TC71-MA colon cancer, whereas a methionine-free diet, alone or in combination with ethionine, prolonged the survival of mice by 2-fold and 2.8-fold, respectively. When all three approaches were combined, survival was prolonged by 3.3-fold. Doxorubicin did not affect the growth of SCLC6, a MDR1-MRP-expressing tumor. A Met-deprived diet and ethionine slightly decreased SCLC6 growth and, in combination with doxorubicin, an inhibition of 51% was obtained, with survival prolonged by 1.7-fold. Combined treatment produced greater tumor growth inhibition (74%) in SCLC6-Dox, a SCLC6 tumor pretreated with doxorubicin. Growth of SNB19 glioma was not inhibited by carmustine, but when it was combined with Met depletion, survival duration was prolonged by 2-fold, with a growth inhibition of 80%. These results indicate the potential of Met depletion to enhance the antitumoral effects of chemotherapeutic agents on drug-refractory tumors.
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PMID:Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drug-resistant human tumor xenografts. 1069 May 50

The relation between the effect of glutathione(GSH)-modulating compounds and platinum compounds (Cisplatin, Nedaplatin)-induced cytotoxicity was investigated. Pretreatment of human glioblastoma (T98G, U87MG) and glioma (KG1C) cell lines with L-buthionine-[S,R]-sulfoximine, which decrease the intracellular GSH concentration, remarkably increased their sensitivity against platinum compounds, whereas pretreatment with N-acetyl-L-cysteine, which increase the intracellular GSH concentration, only marginally protected the cells from the cytotoxic effect of platinum compounds. The results suggest that platinum compounds-induced cytotoxicity can be modified by GSH-modulating compounds in glioblastoma and glioma cell lines.
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PMID:Effect of glutathione-modulating compounds on platinum compounds-induced cytotoxicity in human glioma cell lines. 1069 65

Cisplatin is commonly used for the treatment of malignant brain tumors. However, the mechanisms of cell death by cisplatin are not fully understood. Therefore, the present study was designed to elucidate the apoptotic signaling pathway(s) activated by cisplatin in a C6 rat glioma cell line. C6 cells were treated with various concentrations of cisplatin (0.2-10 microg/ml) for 24-72 h. At 10 microg/ml cisplatin, over 90% of the cells became dead at 72 h. Apoptotic death was confirmed by condensation and fragmentation of nuclei, and DNA laddering. Even in cells treated with 1.5 microg/ml cisplatin, typical apoptotic cells were observed at 72 h. The intracellular level of ceramide, measured Escherichia coli diacylglycerol kinase markedly increased during 24-72 h after the addition of 10 microg/ml cisplatin. The activity of caspase-3(-like) proteases increased and reached a peak at 48 h. Inhibitors of caspases reduced the number of apoptotic cells. Pretreatment of C6 cells with glutathione or N-acetyl-cysteine, which are known to block the activation of neutral magnesium-dependent sphingomyelinase, inhibited ceramide formation, leading to suppression of both activation of caspase-3(-like) proteases and apoptosis by cisplatin. In contrast, pretreatment of the cells with N-oleoylethanolamine (OE), a ceramidase inhibitor, potentiated apoptosis induced by cisplatin. Furthermore, OE enhanced sensitivity of the cisplatin-resistant cells to cisplatin. These results suggest that ceramide is closely implicated in apoptosis of glioma cells by cisplatin through activation of caspase-3(-like) proteases.
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PMID:Role of ceramide during cisplatin-induced apoptosis in C6 glioma cells. 1145 Nov 99

Cisplatin (CDDP) is an efficient DNA-damaging antitumor agent employed for the treatment of various human cancers. CDDP activates nuclear as well as cytoplasmatic signaling pathways involved in regulation of the cell cycle, damage repair and programmed cell death. Here we report that CDDP also activates a membrane-integrated protein, the epidermal growth factor receptor (EGFR). We show that EGFR is activated in response to CDDP in various types of cells that overexpress the receptor, including transformed human glioma cells and human breast tumor cells. CDDP-induced EGFR activation requires its kinase activity, as it can be blocked by an EGFR kinase inhibitor or by expression of a kinase dead receptor. We also show that CDDP-induced EGFR activation is independent of receptor ligand. CDDP induces the activation of c-Src, and EGFR activation is blocked by Src-family inhibitor PP1, suggesting that Src kinases mediate CDDP-induced EGFR activation. We propose that EGFR activation in response to CDDP is a survival response, since inhibition of EGFR activation enhances CDDP-induced death. These findings show that signals generated by DNA damage can modulate EGFR activity, and argue that interfering with CDDP-induced EGFR activation in tumor cells might be a useful approach to sensitize these cells to genotoxic agents.
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PMID:Cisplatin-induced activation of the EGF receptor. 1248 25

Gamma-glutamyltransferase (GGT) hydrolyses gamma-glutamylated peptides, including glutathione and transports amino acids into the cells. The enzyme is up-regulated in some tumors, especially those with a higher degree of malignancy and resistance to cytostatics. In this study we examined the effects of Cisplatin (1.6 x 10(-5)M) on the activity of GGT in astrocytic C6 glioma cells in cultures monitored for growth, morphology and differentiation. Initially (24 h), the drug inhibited cell division and later (96 h), it caused apoptotic death of about half of the population. The more resistant and surviving cells became hypertrophic and more differentiated, as indicated by their larger size and higher protein content, including the maturation- specific GFAP. In addition, the activity of GGT was significantly elevated in these cells at 48 h and onwards. At 96 h, the biochemically determined enzyme activity was between 230% and 330% above the controls. Compared to the protein content, the GGT activity started to increase later (48 h) but it grew steeper towards 72-96 h. Similarly, histochemical analysis revealed a manifold increase in the number of GGT+ cells in the population and higher intensity of staining per cell from at 48 h and onwards. The study showed that the transformed astrocytic cells can up-regulate GGT activity as part of an adaptation and/or, survival-enhancing reaction triggered by Cisplatin.
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PMID:Cisplatin induced gamma-glutamyltransferase up-regulation, hypertrophy and differentiation in astrocytic glioma cells in culture. 1279 79

Cisplatin activates multiple signal transduction pathways associated with cell survival and apoptosis in various cell types. The present study was undertaken to determine the role of extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein kinase family, in cisplatin-induced apoptosis in human glioma cells. Cisplatin resulted in apoptosis in a dose- and time-dependent manner. Cisplatin-induced apoptosis was prevented by the hydrogen peroxide scavenger pyruvate and the antioxidant N-acetylcysteine, but not by the superoxide scavenger tiron. Western blot analysis demonstrated that cisplatin treatment induced time-dependent activation of ERK, which was inhibited by chemical inhibitors of the MEK signaling pathway (PD98059 and U0126) and N-acetylcysteine. These inhibitors prevented cisplatin-induced cell death. Transient transfection of constitutive active MEK1 increased cisplatin-induced apoptosis. Cisplatin resulted in a reduction in mitochondrial membrane potential and its effect was prevented by N-acetylcysteine and PD98059. Caspase inhibitors (Boc-D-FMK and zDEVD-FMK) protected against cisplatin-induced cell death. Cisplatin-induced activation of caspase-3 was inhibited by N-acetylcysteine and PD98059. Taken together, these findings suggest that the ERK activation plays an active role in mediating cisplatin-induced apoptosis of human glioma cells and functions upstream of mitochondrial dysfunction and caspase activation to the initiate the apoptotic signal.
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PMID:Role of ERK activation in cisplatin-induced apoptosis in A172 human glioma cells. 1547 10

Flavonoids are a family of polyphenolic compounds found ubiquitously in fruits and vegetables as well as in food products and beverages derived from plants. Baicalein is a flavonoid extracted from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in Oriental medicine. Baicalein exerts either proapoptotic or anti-apoptotic effects in different cell types. The present study was, therefore, undertaken to examine the effect of baicalein on cisplatin-induced apoptosis of human glioma cells. Cisplatin resulted in cell death in a dose- and time-dependent manner and the cell death was attributed to apoptosis. Baicalein prevented loss of cell viability and apoptosis induced by cisplatin in a dose-dependent fashion over the concentrations of 2-10 microM. Exposure of cells to baicalein without cisplatin did not affect cell viability. Western blot analysis demonstrated that cisplatin induced activation of extracellular signal-regulated kinase (ERK), which was not affected by baicalein. Baicalein prevented Bax expression, mitochondrial depolarization, cytochrome c release from mitochondria, and caspase activation induced by cisplatin. Taken together, these findings suggest that baicalein prevents cisplatin-induced apoptosis through inhibition of the mitochondrial depolarization in human glioma cells.
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PMID:Beneficial effect of flavonoid baicalein in cisplatin-induced cell death of human glioma cells. 1591 Nov 24

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.
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PMID:Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies. 1613 28


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