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)

Membrane-modifying agents such as reserpine, calcium antagonists (nicardipine, verapamil) and calmodulin inhibitor (trifluoperazine) were found to enhance the cytotoxicity of ACNU in vitro and in vivo in ACNU-resistant C 6 (C 6/ACNU) glioma. In in vitro experiments, uptake and retention studies with [14C] ACNU revealed that intracellular uptake and retention of ACNU in C 6 cells were larger than those in C 6/ACNU cells, and that these membrane-modifying agents increased the cellular uptake and retention of ACNU in C 6, especially in C 6/ACNU cells. The amount of ACNU in C 6/ACNU cells reached the same level as that detected in C 6/ACNU cells. When these drugs were added along with ACNU at the concentration of 10 to 20 microM to the culture in vitro, ACNU resistance was completely overcome. In in vivo experiment, reserpine, nicardipine, verapamil and trifluoperazine in doses 250 to 500 micrograms/kg intrathecally administered with 1 mg/kg ACNU 1 day after the tumor inoculation significantly enhanced the chemotherapeutic effect of ACNU in C 6/ACNU bearing (C 6/ACNU-MG) rats. It might be concluded that the mechanism of enhancement of ACNU cytotoxicity presented in in vitro and in vivo is explained by the enhanced accumulation of ACNU by these membrane-modifying agents in C 6, especially in ACNU-resistant (C 6/ACNU) cells, and, furthermore, that combination chemotherapy with ACNU and such membrane interacting drugs as reserpine, calcium antagonists (nicardipine, verapamil) and calmodulin inhibitor (trifluoperazine) could lead to the capability of overcoming resistance to ACNU in glioma.
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PMID:[Possibility of overcoming of ACNU resistance in an ACNU-resistant subline of C6 rat glioma]. 346 59

A calmodulin inhibitor, trifluoperazine, was found to enhance the cytotoxicity of ACNU in vitro in rat C6 glioma, 9L gliosarcoma and their ACNU-resistant sublines (C6/ACNU and 9L/ACNU). Uptake and retention of ACNU in these cells were studied with [14C]ACNU in the absence or presence of trifluoperazine. The results indicated that intracellular uptake and retention of ACNU in C6 and 9L cells were larger than those in C6/ACNU and 9L/ACNU cells, and that trifluoperazine increased the cellular uptake and retention of ACNU in C6 and 9L, especially in C6/ACNU and 9L/ACNU cells. The amounts of ACNU in C6/ACNU and 9L/ACNU cells reached almost the same level as those detected in C6 and 9L cells. When trifluoperazine were added along with ACNU to the culture in vitro at a concentration of 10 and 20 microM, ACNU resistance was completely overcome. Furthermore, treatment of C6 and C6/ACNU cells with 20 microM trifluoperazine did not change the cellular uptake rate of [14C]AIB (alpha-aminoisobutyric acid), which might indicate that the membrane permeability of the cells was kept intact during the drug treatment. The same phenomenon was observed in 9L and 9L/ACNU cells. It might be concluded that the enhanced effect of cytotoxicity of ACNU in ACNU-resistant rat brain tumor cells presented in this study is presumably due to the increase of intracellular concentration of ACNU resulting from the inhibition of the efflux of ACNU by trifluoperazine from the resistant cells. It was also suggested that ACNU resistance in malignant brain tumors could be overcome by combination chemotherapy with ACNU and calmodulin inhibitors.
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PMID:[Possibility of overcoming ACNU resistance in ACNU-resistant sublines of rat brain tumors in vitro by a calmodulin inhibitor]. 347 Jun 26

Sister chromatid exchanges (SCEs) induced by four anticancer drugs, 3-(4-amino-2-methyl-5-pyrimidyl) methyl-1-(2-chloroethyl)-1-nitrosourea (ACNU), 1-3-bis (2-chloroethyl)-1-nitrosourea (BCNU), nitrogen mustard (HN2), cis-diamminedichloroplatinum (II) (cis-Pt) were examined on five cell lines derived from human malignant glioma biopsy specimens, and compared to results obtained with colony-forming efficiency (CFE) assay. Treatment of the five cell lines with these four drugs produced concentration-dependent increases in SCEs. Treatment with ACNU induced the most SCEs in SF-126 cells decreasing in SF-268 cells followed by SF-210 cells, SF-295 cells, and the least SCEs in SF-188 cells. The results of the SCE assay with BCNU in these cell lines were similar with ones with ACNU. In contrast to results obtained with nitrosoureas, the most SCEs were induced in SF-188 cells and the least were induced in SF-126 cells by the treatment of HN2. The frequency of SCEs induced with cis-Pt was almost similar in the five cell lines. The number of SCEs induced by the treatment of ACNU, BCNU, HN2 and cis-Pt in five cells lines showed a good correlation with cytotoxicity measured by CFE assays, and induction of SCEs occurred at much lower concentrations of these anticancer drugs than those required to induced cell kill. These results suggest that measurement of induced SCEs in human brain tumor cells treated with some anticancer drugs provide a more sensitive indicator of drug action than CFE assay and that SCE assays may be a useful method of the in vitro sensitivity test to some anticancer drugs.
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PMID:[Anticancer drug induced sister chromatid exchange and correlation to cell survival in human brain tumor cells]. 347 31

A calmodulin inhibitor, trifluoperazine, was found to enhance the cytotoxic action of ACNU in C6, especially in ACNU-resistant (C6/ACNU) glioma cells in vitro. In order to clarify the efficacy of trifluoperazine in vivo, 1 X 10(7) C6 or C6/ACNU cells were percutaneously implanted into the cisterna magna of Wistar rats to produce meningeal gliomatosis (MG) models as a chemosensitivity assay system. MG rats were treated with ACNU and trifluoperazine according to a variety of schedules. Trifluoperazine in doses of 250 to 500 micrograms/kg intrathecally (it) administered with 1 mg/kg ACNU 1 day after the tumor inoculation significantly increased the life span of the C6/ACNU bearing (C6/ACNU MG) rats. At doses of 250 and 500 micrograms/kg of trifluoperazine in the C6/ACNU MG rats, values of increased life span of 22 and 30% were obtained with a 1 mg/kg dose of ACNU, respectively. These values were statistically significant compared with that obtained in the C6/ACNU MG rats treated with ACNU alone at 1 mg/kg. It might be concluded that the combination chemotherapy with ACNU and such a calmodulin inhibitor as trifluoperazine could overcome ACNU resistance in malignant brain tumors.
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PMID:[Overcoming of ACNU resistance in an ACNU-resistant subline of rat C6 glioma in vivo through enhanced effect of ACNU by calmodulin inhibitor]. 347 42

The purpose of this study was to investigate the cell cycle perturbation of cultured C6 rat glioma cells induced by 1-(4-amino-2-methyl-5-pyrimidyl)methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU) using simultaneous flow cytometric measurements of DNA and bromodeoxyuridine (BrdU) content. A new graphic computer program permitted the quantification of cell density in hexagonal subareas and allowed the fraction of BrdU-labeled cells with mid-S phase DNA content (FLS) to be defined in a narrow window. The cell kinetic parameters such as cell cycle time (Tc) and S phase time (Ts) were estimated from a manually plotted FLS curve at 18 and 6 hr, respectively. The major effect of ACNU on the cell cycle was an accumulation of the cells in the G2M phase 12 to 24 hr posttreatment when compared to G2M traverse of untreated cells. For the two-dimensional analysis, cells were labeled with BrdU and then treated with ACNU, or treated with ACNU and then labeled with BrdU. It was concluded that the cells in the S and G2M phases at the time of ACNU administration progressed to mitosis but that the G1 phase cells accumulated in the subsequent G2M phase. Two-dimensional FCM analysis using BrdU provided a useful tool in studying cell cycle perturbation.
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PMID:Cell cycle perturbation of cultured C6 glioma cells following short-term contact with a low dose of ACNU. 347 87

The antitumor compound ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride) is widely used for treatment of malignant brain tumors. The authors have investigated the mechanism of acquisition of ACNU resistance at the cellular level by isolating ACNU-resistant mutants from V79 Chinese hamster cells and C6 rat glioma cells after treatment of the cells with ACNU or other alkylating agents. In V79 Chinese hamster cells, ACNU at 1 to 4 micrograms/ml caused dose-dependent induction of drug-resistant mutants to ACNU (10 micrograms/ml) and 8-azaguanine (20 micrograms/ml), but not to ouabain (1 mM). Values for the mean lethal dose of ACNU-resistant mutants were 2.4 to 17.2 times those of the parent V79 cells. The ACNU-resistant phenotype was stable during an observation period of 13 weeks. The ACNU seemed to have a specific effect in inducing ACNU-resistant mutations, because no ACNU-resistant mutations were induced by treatment of the cells with other known mutagens, such as N-methyl-N'-nitro-N-nitrosoguanidine, methylmethanesulfonate, and ethylmethanesulfonate. The C6 rat glioma cells also showed a significant mutagenic response to ACNU, producing ACNU- and 5-fluorouracil-resistant mutants. The present results have the important therapeutic and mechanistic implication that ACNU is a potent mutagen and induces mutants that are resistant to ACNU and to other drugs.
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PMID:Specific induction of ACNU-resistance in V79 Chinese hamster cells and C6 rat glioma cells. 347 13

The effects of combination chemotherapy of ACNU and 5-FU on cells grown exponentially as monolayers, cells in multi-cell spheroids and in s.c. transplanted tumors of rat glioma clone-6 cells were analyzed by the colony-forming assay. The cytotoxic effect of ACNU on cells in spheroids was enhanced by continuous 5-FU pretreatment for several hours, but further enhancement was obtained only if the 5-FU pretreatment lasted for more than 12 hr. The combined effect was decreased by a drug-free interval due to recovery from potentially lethal 5-FU damage, but ACNU treatment immediately after 5-FU treatment suppressed PLD recovery. Analysis with sequential trypsinization of spheroids indicated that ACNU showed more marked cytotoxicity on cells in the deeper layers in spheroids than on those in the outer layers, whereas the effect of 5-FU decreased towards the deeper cell layers. Enhancement of treatment with ACNU combined with 5-FU was evident for cells in the outer layers, but was more remarkable in the deeper layers. The combined effect of ACNU and 5-FU on s.c. tumors was similar to that in spheroids. The effect of combined treatment of ACNU with 5-FU on increase in body weight was within the additive range of both drugs acting independently, but was more than additive for the growth delay of s.c. tumors.
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PMID:Experimental combination chemotherapy of ACNU and 5-FU against cultured glioma model (spheroid) and subcutaneous rat glioma. 347 9

In order to study the mechanism of the resistance to chemotherapeutic agents, especially ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride), two variant cell lines (C6/ACNU and 9L/ACNU) resistant to ACNU were selected in vivo from rat C6 and 9L glioma, respectively. Uptake and efflux of ACNU in these resistant cells were studied with Ethylene[14C]ACNU. The result indicated that the resistance exhibited by both sublines were due to both the reduced uptake of the drug and the increased efflux. The study of the effects of oxidative phosphorylation inhibitor, DNP (2,4-dinitrophenol), on the uptake and retention of ACNU suggested that there is an active outward transport mechanism for ACNU in both glioma sublines and that enhanced activity of this efflux mechanism renders cells highly resistant to the cytotoxic action of ACNU. In an attempt to clarify the more detailed biochemical mechanisms of this active efflux system, we surveyed various membrane-modifying agents which potentiate the sensitivity of these resistant cells to ACNU. Among a number of membrane-modifying agents, reserpine was found to retain ACNU in the resistant cells and to enhance the action of ACNU on these resistant cell lines. It may be concluded that drugs such as reserpine may overcome a mechanism of ACNU resistance.
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PMID:The mechanism and overcoming of resistance in ACNU-resistant sublines of C6 and 9L rat glioma. 347 34

For the purpose to study reasonable treatment for recurrent gliomas, in vitro immunochemosensitivity tests were performed by using human malignant glioma cell line (ONS-12) and its ACNU-resistant cell line (ONS-12/ACNU), which were established in our laboratory. ONS-12/ACNU cells showed a cross-resistance to Ara-C, but not for cisplatin and methotrexate. The lymphokine-activated killer (LAK) cells induced in vitro from the peripheral blood lymphocytes (PBL) of healthy subjects, showed stronger cytotoxicity to ONS-12/ACNU than ONS-12 cells. From these data, selection of appropriate anti-tumor agents on the in vitro sensitivity tests was a most useful method for the treatment of recurrent gliomas, and the adoptive immunotherapy with LAK cells may be useful for ACNU-resistant gliomas.
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PMID:[Experimental studies on the treatment of recurrent gliomas]. 349 51

Establishment and its characteristics of a nude mice solid tumor model NHG-1 from human glioma cell line are reported. 5-8 week old NC nude mice of both sexes and SHG-44 cell line used in this experiment were from our laboratory. The initial successful transplantation rate was 7/11 (64%) and that of 30 passages in the subsequent 4 years was 100%. After subcutaneous inoculation, growth curve showed a latent period in week 1-2, slow growing period in week 3-4, rapid growing period in week 5-6 and a final plateau period in week 7. The doubling time was 7 days and cell cycle time was 2.5 days. The cells in G1, S and G2M phases comprised 56%, 27% and 17%, respectively. The survival time of the host was 54 +/- 15 days. The tumor tissues showed a tendency towards invading the surrounding soft tissues. By morphological observation with light and electron microscopes, LDH isozyme assay, PAP immuno-histochemistry labelling GFAP and chromosome analysis, it is confirmed that the transplantable tumor possesses the characteristics of human malignant glioma. The estrogen receptor in the transplantable tumors demonstrated by cytochemical assay indicates that the glioma carcinogenesis is related to endocrine factor of the host. The therapeutic effects of anticancer drugs, such as ACNU, BCNU and 10-hydroxy-2-decenoic acid from the royal jelly on NHG-1 model are evaluated.
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PMID:[Establishment of human glioma cell line--nude mice solid tumor model NHG-1 and its characteristics]. 367 17


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