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)

The goal of this study was to determine the antitumor activity and toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus recombinant interferon-alpha (IFN-alpha) in patients with recurrent glioma. As single agents, both BCNU and IFN-alpha can cause tumor regression in patients with recurrent glioma. In vitro studies suggest synergy between the two agents. Thirty-five patients in whom computerized tomography (CT) or magnetic resonance (MR) evidence was obtained of progressive astrocytoma, oligoastrocytoma, or oligodendroglioma received recombinant IFN-alpha 2a (12 x 10(6) U/m2 intramuscularly) on Days 1 through 3 and BCNU (150 mg/m2 intravenously) on Day 3 of each 6-week cycle. All patients had tumor progression despite radiation therapy and had received no prior chemotherapy. Response was assessed by CT or MR evidence and by neurological examination while the patients were on a regimen of stable or decreasing doses of corticosteroids. All patients could be evaluated for response and toxicity. Twenty-nine percent of the patients demonstrated objective tumor regression; 37% remained stable for more than 6 months and 25% were stable for less than 6 months. The median duration of response to IFN-alpha and BCNU was 9.9 months and the median survival for all patients was 13.3 months. Toxicity consisted primarily of moderate myelosuppression, venous irritation, vomiting, flulike symptoms, and transient reversible exacerbation of underlying neurological symptoms. The use of BCNU plus IFN-alpha is a safe, active regimen in the treatment of patients with recurrent glioma who have failed to respond to prior radiation therapy. The contribution of IFN to the antitumor activity observed in this study compared with that previously described with BCNU alone cannot be assessed from this trial.
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PMID:Phase II evaluation of recombinant interferon alpha and BCNU in recurrent glioma. 786 Dec 21

Expression of the O6-methylguanine DNA methyltransferase (MGMT) gene in human glioma cell lines is strongly associated with resistance to the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea. To examine the possibility that methylation of the body and promoter regions of the MGMT gene is associated with MGMT expression in a graded, rather than a completely on/off fashion, the present study analyzed the methylation status of the MGMT gene in human glioma cell lines exhibiting a wide range of MGMT expression. Methylation in the body of the gene was uniform within each cell line and correlated directly with MGMT expression. The level of MGMT promoter methylation was also graded across the cell lines, at 21 of 25 CpGs tested, but correlated inversely with MGMT expression. Two sites in the MGMT promoter were also much more accessible to restriction enzyme digestion, and thus in a more open chromatin conformation, in nuclei from high MGMT expressors relative to nuclei from cells with little or no MGMT expression. We conclude that the level of methylation, in both the body and promoter of the MGMT gene, is associated with MGMT expression in a graded fashion and may be important in setting the transcriptional state of the MGMT promoter through changes in chromatin structure.
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PMID:Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. 800 31

We have examined the formation of DNA in rat glioma cells. Cytotoxicity was induced in the cells using BCNU (1,3-bis(2-chloroethyl)-1-nitroso-urea) in the presence or absence of CPZ (chlorpromazine). There was impaired formation of DNA in cells treated with BCNU. This was further enhanced in cells treated with both BCNU and CPZ. In the latter case we did not find any intact high molecular weight DNA.
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PMID:Reduced formation of high molecular weight DNA in murine gliomas treated with nitrosourea and chlorpromazine. 807 63

Resistance to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU), an experimental anticancer compound, was investigated in the chloroethylnitrosourea-sensitive Mer- SK-MG-1 and -resistant Mer- SKI-1 human glioma cell lines. The transport of [3H]SarCNU was examined in suspension. The uptake of [3H]SarCNU was found to be temperature dependent in SK-MG-1 and SKI-1, but less so in SKI-1. At 37 degrees C, uptake of 50 microM [3H]SarCNU was linear up to 4 s in both cell lines, with uptake being significantly faster in SK-MG-1 than in SKI-1 under initial rate conditions. There was no significant difference in the rate of influx at 22 degrees C between both cell lines. Equilibrium was approached after 1 min at 22 and 37 degrees C. At 37 degrees C, steady state accumulation of SarCNU at 30 min was reduced significantly (35%) in SKI-1 cells compared with SK-MG-1 cells, although accumulation was similar at 22 degrees C. In SK-MG-1 cells, uptake of [3H]SarCNU at 37 degrees C was found to be saturable, but uptake in SKI-1 cells was not saturable over a 1000-fold range of concentrations. Analysis of efflux in cells preloaded with 50 microM [3H]SarCNU revealed that the rate of efflux was equivalent in both cell lines but that the efflux rate was more rapid at 37 degrees C compared with 22 degrees C. Metabolism of SarCNU at 37 degrees C was not different in either cell line after a 60-min incubation, as determined by thin layer chromatography. SKI-1 cells, compared with SK-MG-1 cells, were 3-fold more resistant to SarCNU at 37 degrees C but only 2-fold more resistant at 22 degrees C, a temperature at which SarCNU accumulation was similar in both cell lines. The 2-fold resistance at 22 degrees C was similar to that of 1,3-bis(2-chloroethyl)-1-nitrosourea at 37 and 22 degrees C. These findings indicate that increased cytotoxicity in SK-MG-1 cells is associated with a greater accumulation of SarCNU via an epinephrine-sensitive carrier that is not detectable in SKI-1 cells. However, part of the chloroethylnitrosourea resistance in SKI-1 cells is not secondary to decreased accumulation.
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PMID:Altered cytotoxicity of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea in human glioma cell lines SK-MG-1 and SKI-1 correlates with differential transport kinetics. 813 53

O6-Alkylguanine-DNA alkyltransferase (AT) is a cellular protein that protects cells from the cytotoxic effects of nitrosoureas by repairing alkyl lesions at the O6 position of guanine. We have studied the ability of O6-benzylguanine to deplete AT activity in brain tumor xenografts and thereby increase the sensitivity of these tumors to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In toxicity studies, pretreatment of athymic mice with O6-benzylguanine increased the toxicity of BCNU significantly. After i.p. injection of O6-benzylguanine into athymic mice carrying subcutaneous (s.c.) D341MED, a human medulloblastoma xenograft with a high AT activity, the AT activity of the tumors became undetectable within 1 h and remained depleted until 36 h. In s.c. xenografts to D341MED, treatment with O6-benzylguanine followed 1 h later by BCNU produced a significantly greater growth delay (14.8 days) than was seen with BCNU alone (2.3 days). A lower pretreatment dose of O6-benzylguanine produced a significantly smaller therapeutic effect. Delaying the administration of BCNU until 36 h after O6-benzylguanine resulted in a growth delay (1.2 days) that was not significantly different from that produced by the control or BCNU alone. In athymic mice with intracranial (i.c.) xenografts of D341MED, pretreatment with O6-benzylguanine followed 1 h later by BCNU produced a significantly increased survival as compared with that of the control, BCNU alone, O6-benzylguanine alone, and O6-benzylguanine followed 36 h later by BCNU. In experiments with s.c. xenografts of D245MG, a human glioma xenograft with undetectable AT activity, pretreatment with O6-benzylguanine 1 h prior to BCNU produced a significantly greater effect than was seen with BCNU treatment alone. The combination regimen, however, was not as effective as an equitoxic dose of BCNU alone. These studies suggest that O6-benzylguanine may be a useful adjuvant to nitrosourea therapy in human malignancies that exhibit a range of AT activities and that dose and timing are important variables in achieving therapeutic success. These data also indicate that therapeutic potentiation of BCNU by O6-benzylguanine can be achieved in i.c. tumors. As a result, this approach may be useful in the treatment of neoplasms of the central nervous system.
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PMID:Treatment of subcutaneous and intracranial brain tumor xenografts with O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea. 825 96

SKI-1 is a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioma cell line and SK-MG-1 is a BCNU-sensitive glioma cell line. Both cell lines do not express O6-methylguanine-DNA methyl transferase (MGMT) and exhibit comparable levels of 3-methyladenine DNA glycosylase. In order to detect DNA binding proteins involved in alternative DNA repair mechanisms of BCNU damage, we performed Southwestern analysis using a DNA probe damaged with BCNU and nuclear protein extracts from SKI-1 and SK-MG-1 cell lines. Both cell lines express a protein of M(r) 116,000 that is able to bind to BCNU-damaged DNA with higher specificity than to undamaged DNA. This protein was identified as poly(ADP-ribose) polymerase (PARP). Using glioma extracts depleted of PARP or using antibody to block the DNA binding domain of PARP no other protein binding to BCNU-treated probe was observed. Addition of methoxyamine, an inhibitor of DNA strand breaks, led to a significant reduction of PARP binding to BCNU-treated DNA. BCNU treatment of both glioma cell lines led to reduced nicotinamide adenine dinucleotide levels, indicating activation of PARP. Thus, the recognition and binding of PARP to BCNU-induced DNA nicks with concomitant PARP activation may be important processes that are involved in the initial stage of DNA repair of BCNU lesions in glial cells.
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PMID:Identification of a 116 kDa protein able to bind 1,3-bis(2-chloroethyl)-1-nitrosourea-damaged DNA as poly(ADP-ribose) polymerase. 853 47

The effect of the O6-alkylguanine-DNA alkyltransferase (AGT) inhibitor, O6-benzylguanine (O6-BG), on the anti-tumour activity of 8-carbamoyl-3-methylimidazo [5,1-d]-1,2,3,5-tetrazine-4(3H)-one (temozolomide) or 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) was evaluated in athymic mice bearing subcutaneous (s.c.) human glioma (U87MG) xenografts. The activity of AGT in U87MG xenografts was 4.3 +/- 1.5 fmol mg-1 protein (mean +/- s.d). These xenografts were inherently sensitive to treatment with alkylating compounds alone, with non-toxic doses of temozolomide (35 mg kg-1) or BCNU (10 mg kg-1) producing tumour growth delays of 23.3 and 11.8 days respectively. O6-BG (40 mg kg-1) did not inhibit tumour growth when administered alone, but was found to enhance significantly the anti-tumour activity of temozolomide or BCNU when administered 1 h before therapy (P < 0.002, Mann-Whitney test). AGT activity measured 24 h after the administration of 40 mg kg-1 O6-BG, was only 0.9 +/- 0.2 fmol mg-1 protein. These results are in contrast to previous studies in vitro with tumour cell lines of low AGT activity (< 15 fmol mg-1 protein), in which the cytotoxicity of temozolomide or BCNU was unaffected by AGT depletion.
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PMID:O6-benzylguanine enhances the sensitivity of a glioma xenograft with low O6-alkylguanine-DNA alkyltransferase activity to temozolomide and BCNU. 862 62

Glutathione (GSH) depletion by buthioninine sulfoximine (BSO) is being explored clinically as a means of enhancing the efficacy of cancer chemotherapy. We investigated the kinetics of GSH depletion and altered gamma-L-glutamyl-L-cysteine synthetase (gamma-GC-S) gene expression in two human malignant glioma cell lines, HBT5 and HBT28, and examined how these relate to GSH resynthesis and changes in DNA interstrand cross-link induction and cytotoxicity of 1,3-bis(2-chloroethyl)-nitrosourea (BCNU). GSH content was 54 and 126 nmol/mg/protein in HBT 5 and HBT 28, respectively, and after a 24-hr exposure to 100 microM BSO was decreased by 95% in HBT 5 and 91% in HBT 28. Basal gamma-GC-S enzyme activity in HBT 28 was twice that in HBT 5, and steady state gamma-GC-S gene transcripts were 2.6-fold higher in HBT 28 than in HBT 5, with no apparent amplification or rearrangement of the gene in either cell line. BSO exposure (100 microM) for 24 hr increased gamma-GC-S gene transcripts by 1.7-fold in HBT 5 and 2.8-fold in HBT 28. After BSO removal, the rate of GSH resynthesis in HBT 28 was twice that in HBT 5. Continuous BSO exposure increased the level of BCNU-induced DNA interstrand cross-links, and cytotoxicity was significantly higher in cells exposed continuously to BSO than in cells with only a 24-hr BSO preexposure. This increase was, however, greater in HBT 28 than in HBT 5. These findings indicate significant heterogeneity in the effects of BSO on gamma-GC-S gene expression and in the ability of BSO to sensitize tumors and cell lines to BCNU. The data also suggest that by preventing GSH resynthesis, a greater level of cytotoxicity is achieved with continuous BSO exposure than with BSO preexposure alone.
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PMID:Buthionine sulfoximine induction of gamma-L-glutamyl-L-cysteine synthetase gene expression, kinetics of glutathione depletion and resynthesis, and modulation of carmustine-induced DNA-DNA cross-linking and cytotoxicity in human glioma cells. 864 39

In the present study organotypic multicellular spheroids (OMS) were used to study the effects of chemotherapeutic agents on malignant gliomas. Compared with the frequently used cell line models, OMS have several advantages with respect to the preservation of the cellular heterogeneity and the structure of the original tumour. OMS prepared from seven glioma specimens were treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), daunorubicin or doxorubicin. After exposure to these drugs, the histology and cell proliferation of the OMS were analysed by immunohistochemistry and image analysis. Furthermore, the expression of P-glycoprotein (P-gp) and multidrug resistance-related protein (MRP), which both can contribute to resistance to daunorubicin and doxorubicin, were immunohistochemically investigated. We found that OMS from gliomas are sensitive for daunorubicin and doxorubicin but not for BCNU in terms of tissue destruction and decrease in cell proliferation. In addition, all gliomas were P-gp and MRP negative, which is in accordance with the sensitivity for daunorubicin and doxorubicin. Considering the potential use of several new alternative drug delivery methods, such as intratumoural implantation of drug-impregnated polymers or liposomal encapsulation of cytostatic drugs, daunorubicin and doxorubicin might be effective in the treatment of malignant gliomas.
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PMID:Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas. 868 20

1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), one of the chloroethyl nitrosoureas, is effective against malignant glioma. To develop its use in intrathecal chemotherapy, we encapsulated BCNU in hybrid liposomes composed of dimyristoylphosphatidylcholine and micellar surfactants (Tween 20) and dissolved it in artificial cerebrospinal fluid (lipo-BCNU). We then studied the toxicity of hybrid liposomes and cellular proliferation inhibition of lipo-BCNU in vitro. We found that 3 mM hybrid liposomes did not affect the viability of human endothelial cells and that lipo-BCNU inhibited the proliferation of human glioma cell lines U-105MG, U-251MG, and U-373MG, and rat glioma cell lines C6 and 9L in a concentration-dependent fashion. Wistar rats that were administered lipo-BCNU intracisternally showed no weight loss, neurological symptoms, or histological changes of the brain and spinal cord. A Wistar rat model of meningeal gliomatosis was established by intracisternal inoculation of 0.1 ml cell suspension containing 1 x 10(6) or 5 x 10(6) viable C6 glioma cells. Two days after inoculation, lipo-BCNU (BCNU, 2.5 mg/kg) was administered intracisternally. When 1 x 10(6) glioma cells were inoculated (experiments 1 and 2), the median survival times were 24.5 and 26 days in the control groups and 32 and 45 days in the lipo-BCNU-treated groups. respectively. When 5 x 10(6) glioma cells were inoculated (experiments 3-6), the median survival times were 17-29.5 days in the control groups and 23-44 days in the treated groups, respectively. Significantly prolonged survival was obtained in three of six experimental groups. After the administration of 1 ml lipo-BCNU (BCNU, 4.67 mM) or 1 ml BCNU solubilized with 5% dextrose/water (BCNU, 4.67 mM) into the cisterna magna of dogs, the cisterna magna cerebrospinal fluid was sampled, and the BCNU concentrations were assayed by high-performance liquid chromatography. The half-life of the lipo-BCNU was longer than that of BCNU solubilized with 5% dextrose/water. These results suggest that the intrathecal administration of lipo-BCNU may be possible for the treatment of meningeal gliomatosis.
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PMID:Intrathecal chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea encapsulated into hybrid liposomes for meningeal gliomatosis: an experimental study. 875 68


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