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)

Improvement in the treatment of patients harboring malignant glioma will probably be seen as small incremental changes as new modalities of treatment are proposed, tested, and substantiated. Uncontrolled phase II studies may provide hints of efficacy. However, the results must be substantiated in carefully controlled phase III evaluations. The Brain Tumor Study Group of the National Cancer Institute has demonstrated that mithramycin is not effective in the treatment of malignant glioma and the overall median survivorship experience is no different than the 23 weeks found in historic controls. Radiotherapy can bring about a meaningful increase in survival as can 1,3-bis(2-chloroethyl)-1-nitrosourea. The combination appears to produce more long-term survivors than either treatment above. Methyl-1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea does not appear to be additive to radiotherapy but is more effective than no therapy at all. Studies of the oncolytic effect of corticosteroids in contradistinction to their cerebral edema controlling effects are being done and will provide meaningful data on this important symptomatolytic therapy.
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PMID:Brain Tumor Study Group: a survey of current activities. 14 90

A controlled, prospective, randomized study evaluated the use of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or radiotherapy in the treatment of patients who were operated on and had histological confirmation of anaplastic glioma. A total of 303 patients were randomized into this study, of whom 222 (73%) were within the Valid Study Group (VSG), having met the protocol criteria of neuropathology, corticosteroid control, and therapeutic approach. Patients were divided into four random groups, and received BCNU (80 mg/sq m/day on 3 successive days every 6 to 8 weeks), and/or radiotherapy (5000 to 6000 rads to the whole brain through bilateral opposing ports), or best conventional care but no chemotherapy or radiotherapy. Analysis was performed on all patients who received any amount of therapy (VSG) and on the Adequately Treated Group (ATG), who had received 5000 or more rads radiotherapy, two or more courses of chemotherapy, and had a minimum survival of 8 or more weeks (the interval that would have been required to have received either the radiotherapy or chemotherapy). Median survival of patients in the VSG was, best conventional care: 14 weeks (ATG: 17.0 weeks); BCNU: 18.5 weeks (ATG: 25.0 weeks); radiotherapy: 35 weeks (ATG: 37.5 weeks); and BCNU plus radiotherapy: 34.5 weeks (ATG: 40.5 weeks). All therapeutic modalities showed some statistical superiority compared to best conventional care. There was no significant difference between the four groups in relation to age distribution, sex, location of tumor, diagnosis, tumor characteristics, signs or symptoms, or the amount of corticosteroid used. An analysis of prognostic factors indicates that the initial performance status (Karnofsky rating), age, the use of only a surgical biopsy, parietal location, the presence of seizures, or the involvement of cranial nerves II, III, IV, and VI are all of significance. Toxicity included acceptable, reversible thrombocytopenia and leukopenia.
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PMID:Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. 35 4

The effect of 0.0001 to 10 muM 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1 muM dexamethasone on cell proliferation was studied by measuring cell densities in control and drug-treated rat glioma (strain C6) monolayer cultures. When C6 cultures were exposed to 0.01 to 10 muM BCNU, the growth rates decreased for 2 days as control cell populations continued to proliferate at log phase rates. These growth-inhibitory responses were dose dependent and ranged from 20 to 80%, relative to control growth. Subsequently, the growth rates increased and the inhibitory responses ranged from 0 to 12% 4 days later. Cell densities in C6 cultures exposed to 1 muM dexamethasone for 1 day did not differ significantly from controls. Then cell proliferation ceased and the inhibitory response remained at 50% relative to controls in stationary phase. When 0.03 muM BCNU and 1 muM dexamethasone were supplied simultaneously to C6 cultures, a 35% inhibitory response occurred after 1 day. This response did not differ significantly from that observed with 0.03 muM BCNU alone. After 4 days, the inhibitory response did not decrease in cultures containing both drugs, but did decrease to 13% in the 0.03 muM BCNU-treated cultures. In 1 muM BCNU-treated cultures, the response was 66% after 1 day, which decreased to 21% 5 days later. When 1 muM BCNU was supplied to C6 cultures that were pretreated for 1 day with 1 muM dexamethasone, the response was 91% the following day, and this decreased to only 54% 5 days later. Dose-response curves showed that the inhibitory responses after 1 day in these pretreated cultures exposed to 0.001 to 10 muM BCNU increased up to 22% relative to the responses produced by either drug alone. After 5 days, the responses in the pretreated cultures exposed to 0.001 to 1 muM BCNU was 50%, which was similar to the response produced by 1 muM dexamethasone alone. Ultrastructural studies revealed that control and 1 muM BCNU-treated C6 cells contained 18 mitochondria, but the treated cells were 10% smaller after 1 day. Cells exposed to 1 muM dexamethasone for 1 day conount of granular endoplasmic reticulum increased greater than 80% in cells treated with BCNU for 1 day or dexamethasone for 2 days. C6 cells pretreated with dexamethasone and exposed to BCNU for an additional day (a) contained 23 mitochondria, (b) did not decrease in size, and (c) exhibited a greater than 250% increase in the amount of granular endoplasmic reticulum. These results demonstrate that combined growth-inhibitory responses and ultrastructural alterations occur when C6 cells are treated sequentially with 1 muM dexamethasone and BCNU.
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PMID:Combined growth-inhibitory responses and ultrastructural alterations produced by 1,3-bis(2-chloroethyl)-1-nitrosourea and dexamethasone in rat glioma cell cultures. 83 80

RG2 glioma-like cells grown in in vitro culture can be inoculated into rat brains using stereotactic surgical procedures to produce tumors with a diameter of 12-16 mm2 in 20-21 days. This system has been used to evaluate if metoclopramide (MCA) could sensitize the tumor toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). BCNU alone (15 mg/kg, intravenously), and MCA alone (2 mg/kg, intraperitoneally), and these drug treatments in combination, were administered so that BCNU alone was given as a single dose on day 3 after inoculation of the RG2 cells, MCA alone was given on day 3 at 0 and 3 h followed by five or six treatments per week beginning 24 h after the 3 h dose, and BCNU plus MCA were given according to the combined schedule where the first MCA treatment was scheduled 30 min prior to the BCNU infusion. The design of this study required the drug treated animals to be matched to untreated animals (controls) at the time of inoculation of the RG2 cells. Under these experimental conditions, BCNU alone and MCA alone had no effect on tumor growth, whereas BCNU plus MCA significantly retarded brain tumor growth. The normal tissue toxicity induced by BCNU treatment, evaluated by measurement of body weight and survival, was not potentiated by the combination of BCNU plus MCA. These data extend the previous findings of MCA as a radio- and chemosensitizer to include the sensitization of another cytotoxic agent (BCNU) and of another type of tumor (malignant glioma).
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PMID:Metoclopramide as a sensitizer of 1,3-bis(2-chloroethyl)-1-nitrosourea treatment of brain tumors in the rat. 152 8

This Phase III trial tested the efficacy and safety of intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for the treatment of newly resected malignant glioma, comparing intra-arterial BCNU and intravenous BCNU (200 mg/sq m every 8 weeks), each regimen without or with intravenous 5-fluorouracil (1 gm/sq m three times daily given 2 weeks after BCNU). All patients also received radiation therapy. A total of 505 patients were randomly assigned within the study. Fifty-seven patients were excluded, primarily because of neuropathology error, and the remaining 448 patients constituted the Valid Study Group. Of the total 505 patients, 190 patients could not receive intra-arterial BCNU and 315 patients were randomly assigned to receive intra-arterial (167 patients) and intravenous (148 patients) BCNU. Actuarial analysis (log-rank) demonstrated reduced survival for the intra-arterial group (p = 0.03). Serious toxicity was observed in the intra-arterial group; 16 patients (9.5%) developed irreversible encephalopathy with computerized tomography evidence of cerebral edema, and 26 patients (15.5%) developed visual loss ipsilateral to the infused carotid artery. Administration of 5-fluorouracil did not influence survival. The survival rate between the intravenous and the intra-arterial BCNU patients with glioblastoma multiforme did not differ, but was worse for intra-arterial BCNU patients with anaplastic astrocytoma than for those receiving intravenous BCNU (p = 0.002). Neuropathologically, intra-arterial BCNU produced white matter necrosis. It is concluded that intra-arterial BCNU is neither safe nor effective in prolonging survival when administered by the methods used in this study of newly diagnosed patients with malignant glioma.
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PMID:A randomized comparison of intra-arterial versus intravenous BCNU, with or without intravenous 5-fluorouracil, for newly diagnosed patients with malignant glioma. 156 40

The effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on human glioma cell growth was investigated. When incubated with simvastatin, cell proliferation decreased in a concentration-dependent fashion, as measured by cell number and [3H]-thymidine incorporation into DNA (concentration producing 50% inhibition, 60 nM). The effect was detectable 12 h after cells were exposed to the drug and persisted for 2 days. Addition of mevalonate to cells exposed effect of simvastatin in combination with beta-interferon and N,N'-bis(2-chloroethyl)-N-nitrosourea, both antitumoral drugs, was also evaluated by cell growth inhibition assay. The concentration producing 50% inhibition for each of these drugs was 650 units/ml and 50 nM, respectively. Subliminal concentrations of beta-interferon or N,N'-bis(2-chloroethyl)-N-nitrosourea were incubated together with 1 nM simvastatin. The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity. Simultaneous cell exposure to simvastatin with either N,N'-bis(2-chloroethyl)-N-nitrosourea or beta-interferon produced a strong synergistic inhibitory effect on cell proliferation. These data provide in vitro support for the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, utilized as plasma cholesterol-lowering agents, could potentiate the effect of antiblastic drugs on tumor growth.
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PMID:Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect with N,N'-bis(2-chloroethyl)-N-nitrosourea and beta-interferon on human glioma cells. 164 32

The effect of O6-benzylguanine, O6-(p-chlorobenzyl)guanine, and O6-(p-methylbenzyl)guanine on the sensitivity of various human tumor cell lines to alkylating agents is evaluated. The sensitivity of human colon tumor cells, HT29, to the chloroethylating agents, 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 2-chloroethyl(methylsulfonyl) methanesulfonate (clomesone), and chlorozotocin was increased by pretreatment for 2 h with 25 microM of each analogue. O6-Benzylguanine was slightly more effective as a sensitizer in HT29 cells than the p-chlorobenzyl and p-methylbenzyl analogues. However, all analogues sensitized SF767 glioma cells to the cytotoxic effects of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and clomesone to the same degree. Both cell lines were sensitized to the methylating agents streptozotocin and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide, the active intermediate of 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide, by pretreatment with 10 microM O6-benzylguanine for 2 h. The number of Raji cells surviving 50 microM clomesone decreased 3-fold upon pretreatment for 2 h with 1 microM O6-benzylguanine. The degree of enhancement was dependent on the amount of alkyltransferase protein present in cell lines. For example, HT29 cells (alkyltransferase activity, 381 fmol/mg protein) exhibited a greater degree of enhancement when treated with O6-benzylguanine than SF767 (77 fmol/mg protein) and M19-MEL melanoma (36 fmol/mg protein) cells. There was no enhancement observed in mer- cell lines, U251 (less than 2 fmol/mg protein), and BE (3 fmol/mg protein), or with alkylating agents which did not produce a cytotoxic lesion at the O6 position of guanine in DNA such as cisplatin or 4-hydroperoxycyclophosphamide. Our studies suggest that O6-benzylguanine analogues may have utility in mer+ tumors as an adjuvant to a variety of alkylating agents which produce a toxic lesion at the O6 position of guanine.
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PMID:Effect of O6-benzylguanine analogues on sensitivity of human tumor cells to the cytotoxic effects of alkylating agents. 164 66

We have previously shown that O6-benzylguanine can be used to deplete cells of the DNA repair protein O6-alkylguanine-DNA alkyltransferase and to enhance the sensitivity of human glioma (SF767) and colon tumor (HT29) cells to the cytotoxic effects of alkylnitrosoureas. In the present study, the combination of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was evaluated in vitro to determine the number of DNA interstrand cross-links formed and in vivo to compare the therapeutic index with that of BCNU alone. The number of DNA interstrand cross-links, as measured by alkaline elution, was increased in HT29 cells treated with 10 microM O6-benzylguanine for 2 h prior to BCNU exposure compared to cells treated with BCNU only. The number of single strand breaks was not increased by prior exposure to O6-benzylguanine. To evaluate the therapeutic index, HT29 and SF767 cells were grown as xenografts in nude mice and the tumor growth rate after treatment with BCNU alone was compared with the rate after treatment with O6-benzylguanine and BCNU. Treatment was administered i.p. when tumors reached 100-200 mm3. For animals bearing HT29 xenografts that were treated with 60 mg/kg O6-benzylguanine 1 h prior to 20 mg/kg BCNU, the average time for tumor volume to increase by 200% was 25 days, compared to 10 days for animals treated with 20 mg/kg BCNU alone. For animals bearing SF767 xenografts, the tumor growth of controls was not significantly different from that of animals treated with O6-benzylguanine alone or BCNU alone up to the maximally tolerated dose (50 mg/kg). For these 3 groups, the average time for tumors to reach 300 mm3 was 9-12 days. However, when animals were treated with 80 mg/kg O6-benzylguanine 1 h prior to receiving 20 mg/kg BCNU tumor size did not increase for at least 21 days. Our studies demonstrate that the therapeutic index of BCNU can be increased when given in combination with O6-benzylguanine.
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PMID:Effect of O6-benzylguanine on the sensitivity of human tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea and on DNA interstrand cross-link formation. 173 76

Biopsy samples and cultured cells derived from them were obtained from 39 patients with malignant glioma and were analyzed for 1) glutathione (GSH) content; 2) sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or nitrogen mustard (HN2) treatment and 3) the effect of buthionine sulfoximine (BSO) treatment on BCNU and/or HN2 cytotoxicity. The average GSH concentration of biopsy specimens was lower than those of cultured cells (2.36 +/- 0.44 vs. 11.42 +/- 2.32 nmol/10(6) cells). While some of the tumor specimens were sensitive to either BCNU or HN2, the majority were resistant to both. However, 8 of 23 tumors tested showed enhanced sensitivity to BCNU following treatment with BSO. Five of 17 tumors were similarly sensitized to HN2 by BSO. These results suggest that BSO chemosensitization may be of value for certain patients and that screening assays may help identify treatment-sensitive individuals.
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PMID:Glutathione levels and chemosensitizing effects of buthionine sulfoximine in human malignant glioma cells. 174 83

A transient alkalosis of similar magnitude to that observed in vivo has been observed using 31P NMR and 2-deoxy-D-glucose-6-phosphate as a pH marker in a human glioma cell line, SKI-1, with demonstrated sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea. At an effective dose of 5 +/- 1 x 10 micrograms/ml, an increase of 0.13 +/- 0.05 pH units was observed within 4 +/- 1 x 10 min of introducing the drug into the perfusion chamber. Although the in vitro response is of a time course much faster than that in vivo, these results suggest that this immediate pH change could be an indicator of the cytotoxic action of the drug.
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PMID:Alkalosis monitored by 31P NMR in a human glioma cell line exposed to the anti-tumor drug 1,3-bis(2-chloroethyl)-1-nitrosourea. 181 75


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