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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Depletion of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) with O(6)-benzylguanine (O(6)-BG) has been widely shown to enhance 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) activity. This study aimed to determine whether temozolomide, a methylating imidazotetrazinone, would similarly benefit from combination with O(6)-BG. Seven human cell lines were examined with AGT activities ranging from <6 fmol mg-1 protein to >700 fmol mg-1 protein. Comparisons with BCNU were made on both single and multiple dosing schedules, since temozolomide cytotoxicity is highly schedule dependent. In single-dose potentiation studies, cells were preincubated with 100 microM O(6)-BG for 1 h, a treatment found to deplete AGT activity by >90% for 24 h. No potentiation of either temozolomide or BCNU cytotoxicity was observed in two glioblastoma cell lines with <6 fmol mg-1 protein AGT. In all other cell lines studied potentiation of BCNU toxicity by O(6)-BG was between 1.6- and 2.3-fold and exceeded that of temozolomide (1.1- to 1.7-fold). The magnitude of this potentiation was unrelated to AGT activity and the relative potentiation of temozolomide and BCNU cytotoxicity was found to be highly variable between cell lines. In multiple dosing studies two colorectal cell lines (Mawi and LS174T) were treated with temozolomide or BCNU at 24 h intervals for up to 5 days, with or without either 100 microM O(6)-BG for 1 h or 1 microM O(6)-BG for 24 h, commencing 1 h before alkylating treatment. Extended treatment with 1 microM O(6)-BG produced greater potentiation than intermittent treatment with 100 microM O(6)-BG. Potentiation of temozolomide cytotoxicity increased linearly in Mawi with each subsequent dosing: from 1.4-fold (day 1) to 4.2-fold (day 5) with continuous 1 microM O(6)-BG. In contrast, no potentiation was observed in LS174T, a cell line that would appear to be 'tolerant' of methylation. Potentiation of BNCU cytotoxicity increased in both cell lines with repeat dosing, although the rate of increase was less than that observed with temozolomide and continuous 1 microM O(6)-BG in Mawi. These results suggest that repeat dosing of an AGT inhibitor and temozolomide may have a clinical role in the treatment of tumours that exhibit AGT-mediated resistance.
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PMID:Potentiation of temozolomide and BCNU cytotoxicity by O(6)-benzylguanine: a comparative study in vitro. 859 63

The most important prognostic factor in malignant gliomas is histopathological diagnosis of the tumor. The survival of patients with anaplastic astrocytoma is much longer than that of patients with glioblastoma. The median survival of the former has been improved up to almost 4 years by the recent progress of multidisciplinary treatment, whereas that of the latter has still remained in less than 1.5 years. Other important factors proved to be associated with survival of patients with malignant gliomas are the age of patients, Karnofsky performance status on admission, surgery, radiotherapy and chemotherapy. There is substantial evidence suggesting an association between younger patient age and longer survival in adults with supratentorial anaplastic astrocytoma as well as glioblastoma. It is also consistent with evidence that the patients with better performance status on admission live longer after treatment. Gross total resection of supratentorial anaplastic astrocytoma is directly associated with longer and better survival when compared to subtotal or partial resection. For glioblastoma, however, gross total resection has not been proved to have a significant survival advantage over subtotal or partial removal. Radiotherapy has been proved to be associated with longer survival of patients with supratentorial anaplastic astrocytoma and glioblastoma. Chemotherapy has not proved effective in prolonging the survival of patients with glioblastoma. Multidrug chemotherapy with CCNU, procarbazine and vincristine has proved to have significant survival advantage over BCNU alone, suggesting chemotherapy is also a prognostic factor in patients with anaplastic astrocytoma.
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PMID:[Prognostic factors in malignant gliomas]. 867 27

The aim of our study is to characterize the disturbance induced by repeated BCNU treatments in 12 human brain tumor cell lines in terms of their collective behavior. This collective behavior was characterized by means of the Delaunay triangulation and Voronoi mathematical paving techniques combined with the computer-assisted microscope analysis of Feulgen-stained nuclei. This methodology enabled growth to be characterized in terms of cell colony size and density. In addition to this colony pattern characterization, the DNA ploidy level was assessed by means of DNA histogram typing. The cell proliferation level was also determined. Ten astrocytic and two medulloblastoma cell lines treated weekly with BCNU were analyzed. Study of the cell colony architecture and cell proliferation revealed specific BCNU-induced modifications in connection with the origins of the cell lines, i.e. astrocytoma (AST), glioblastoma (GBM), or medulloblastoma (MED). The BCNU-induced effect on GBM (the more malignant of the cell lines) was very different in that proliferation was weakened, but the cell colony density increased after a latency phase. The decrease in cell colony density and cell proliferation of MED seems to indicate that they are more sensitive to BCNU than GBM, but relatively tolerant of this type of chemotherapy in comparison with AST.
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PMID:Computer-assisted microscope characterization of BCNU-induced modifications in the collective behavior of 12 human brain cancer cell lines. 874 May 86

The results of a multi-institutional phase I trial evaluating the safety of surgically implanted biodegradable 1,3-bis(chloro-ethyl)-1-nitrosourea (BCNU) impregnated polymer as the initial therapy for malignant brain tumors are reported. This is the first study of locally delivered BCNU and standard external beam radiation therapy (XRT) given concurrently. Twenty-two patients were treated at three hospitals. The entry criteria were: single unilateral tumor focus larger than 1 cm3; age over 18 years; Karnofsky Performance Score (KPS) of at least 60 h; and an intra-operative diagnosis of malignant glioma. Twenty-one of twenty-two patients had glioblastoma multiforme. After surgery, seven or eight BCNU-loaded polyanhydride polymer discs (7.7 mg BCNU each) were placed in the resection cavity. Postoperatively, all patients received standard radiation therapy; none received additional chemotherapy in the first 6 months. Neurotoxicity, systemic toxicity, and survival were assessed. No perioperative mortality was seen. Neurotoxicity was equivalent to that occurring in other series of patients undergoing craniotomy and XRT without local chemotherapy. Systematically, no significant bone marrow suppression occurred, and there were no wound infections. Median survival in this group of older patients (mean age = 60) was 42 weeks, 8 patients survived 1 year, and 4 patients survived more than 18 months. Interstitial chemotherapy with BCNU-polymer with subsequent radiation therapy appears to be safe as an initial therapy. Several long-term survivors in this group of older patients with predominantly glioblastoma suggests efficacy in some patients. Dose escalation and efficacy trials are planned to further evaluate interstitial chemotherapy for the initial treatment of malignant gliomas.
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PMID:The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. 878 53

Matrix metalloproteinases (MMPs) play an important role in various physiological and pathological conditions such as tissue remodeling, and cancer cell invasion and metastasis. The aim of this study was to determine the effect of the antitumor compounds cis-dichlorodiammine platinum (ii) (cisplatin) and 1, 3 bis (2-chloroethyl)-1-nitrosourea (BCNU) on 72-kDa type IV collagenase activity (MMP-2) in human gliomas. Human glioblastoma cell lines were treated with cisplatin (25 microM), and BCNU (50 microM), and the levels of MMP-2 were estimated in serum-free conditioned medium and in cell extracts at different time intervals. Gelatin zymography revealed increased levels of MMP-2 in serum-free conditioned medium and in cell extracts of untreated glioblastoma cell cultures during a 72-h period. In contrast, MMP-2 levels were significantly decreased in cisplatin-treated cells both in conditioned medium and cell extracts. However, no significant changes of MMP-2 levels were noted in BCNU-treated cells. Quantitative analysis of MMP-2 enzyme activity by densitometry and amount of MMP-2 protein by ELISA showed significantly decreased levels of MMP-2 in cisplatin-treated cells compared to BCNU and untreated glioblastoma cells. The results indicate that decreased levels of MMP-2 might represent an additional mechanism by which cisplatin provides its antineoplastic effects.
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PMID:Effect of cisplatin and BCNU on MMP-2 levels in human glioblastoma cell lines in vitro. 921 24

Glioblastomas extensively invade the surrounding normal brain tissue, with a concomitant expression of various proteolytic enzymes, in particular urokinase-type plasminogen activator (uPA). In this study we used cis-diamminedichloroplatinum (cisplatin) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), commonly used anti-cancer drugs for the treatment of glioblastomas, to study the expression of uPA in three human glioblastoma cell lines in vitro. Cells were treated with 25 microM cisplatin and 50 microM BCNU, and uPA levels were estimated by fibrin zymography during a 72-h time course. Treatment of glioblastoma cells with cisplatin resulted in significantly decreased levels of uPA in serum-free conditioned medium and cell extracts, compared to BCNU-treated and untreated cell lines. Quantitative levels of uPA enzyme activity assessed by scanning laser densitometry and uPA protein by ELISA using antibody against uPA showed decreased levels of uPA in cisplatin-treated glioma cell lines relative to BCNU and untreated cell lines. Our results suggest that anti-tumor compound, cisplatin, may exert its anti-neoplastic effects by inhibiting uPA in malignant glioblastomas.
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PMID:Cisplatin but not BCNU inhibits urokinase-type plasminogen activator levels in human glioblastoma cell lines in vitro. 921 34

The author reviewed treatment results of chemoradiation therapy for malignant brain tumors. For astrocytic tumors, radiation therapy combined with radiosensitizing chemotherapeutic agents, mainly nitrosourea compounds (BCNU or ACNU), has been a standard treatment modality for a long time. The therapy is more effective for anaplastic astrocytoma than glioblastoma. The chemoradiation therapy is now applied for medulloblastoma; it prolonged 5-year survival up to 70%. Metastatic brain tumors are frequently treated by radiation therapy alone. When combined with cisplatin, radiation therapy shows a more excellent antitumor effect.
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PMID:[Chemoradiation for malignant brain tumors]. 938 12

Twenty six (17 males) patients with glioblastoma (GBL), median age 55 years, median Karnofsky Index (KI) 70/100, and 11 patients (9 males) with anaplastic astrocytoma (AA), median age 56 years, median KI 70/100 were treated at recurrence with dibromodulcitol (DBD) 1400 mg/m2 on day 1, BCNU 150 mg/m2 on day 2, and procarbazine (PCZ) 150 mg/day on days 1 to 15. The course was repeated every 4 weeks, but was delayed or decreased by 25% according to hematological toxicity. Response to treatment was evaluated by the criteria of MacDonald et al. (J Clin Oncol 1990; 8: 1277-1280). All GBL-patients were followed until death. One patient with complete response (CR) survived one year, and 2 patients with partial response (PR) survived 1 and 3 years. Ten patients who stabilized (SD) survived 7.5 months, and 13 patients who progressed under chemotherapy had a median survival of 3.5 months. In AA-group 3 patients were alive at the time of the analyses. Six patients: 1 CR and 5 PR survived 6 to 40+ months. Two patients with SD survived 4 and 14 months. Three patients with progressive disease had a mean survived of less than 3 months. The response rate of 55% in AA was significantly higher (p = 0.011) than the 12% response rate seen in GBL. We conclude that the regimen tested appears particularly promising in AA. The results in GBL are comparable to those obtained with a single nitrosourea, despite an increased but reversible toxicity.
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PMID:Response of recurrent glioblastoma and anaplastic astrocytoma to dibromodulcitol, BCNU and procarbazine--a phase-II study. 952 94

Recent data have suggested that mitochondria play a supportive role in maintaining the tumorigenic phenotype. Indeed, antimitochondrial agents have been hypothesized to be potential chemosensitizers to human malignancy. We assessed the utility of this approach by characterizing the antimitochondrial activity of 3,5-di-tert-butyl-4-hydroxybenzylidene-malononitrile (AG17), in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in two human glioblastoma cell lines. AG17 (NSC 242557) is a tyrphostin that has been thought to have some antimitochondrial activity, with limited tyrosine kinase antagonism, and was used at noncytotoxic and nongrowth-inhibitory concentrations (0.25 microM). Glioblastoma cells were incubated in AG17, and changes in mitochondrial activity were determined. Tumor cells became auxotrophically dependent on uridine and pyruvate, indicating the lack of a functioning respiratory chain. Despite this, cells continued to exhibit no growth-inhibitory effects. Exposure to AG17 was associated with significant depolarization of the mitochondrial membrane potential and decreases in mitochondrial mass in both glioblastoma cell lines, correlating with the finding of auxotrophic dependence. In contrast, normal human astrocytes treated with the same dose of AG17 did not show changes in growth, mitochondrial membrane potential, or mass. Indeed, auxotrophic dependence on uridine and pyruvate could not be established in these cells. Glioblastoma cells became significantly more responsive to BCNU chemotherapy with AG17 pretreatment; a linear relationship was noted that correlated the number as well as percentage of polarized mitochondria with glioblastoma cell survival at the highest dose of BCNU used (144 microg/ml). Normal human astrocytes did not change with regard to the dose response to BCNU with previous incubation with AG17. No difference was found in the type of cellular death (apoptosis) in either of the glioblastoma cell lines, with BCNU treatment alone, or with the combination AG17 and BCNU, despite the decrease in polarized mitochondria and mitochondrial mass. AG17 has antimitochondrial properties when used at low dose in human glioblastoma, which are relatively specific to tumor cells when compared with normal astrocytes. The use of AG17 as a chemosensitizer, with drugs such as BCNU, offers a new and possibly effective approach to be developed in patients with glial tumors.
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PMID:Chemosensitization of glioblastoma cells to bis-dichloroethyl-nitrosourea with tyrphostin AG17. 953 47

Previous studies have shown that the negative cell cycle regulator WAF1/Cip1 is often overexpressed in human gliomas and that WAF1/Cip1 overexpression may be a factor in cancer chemoresistance. We established a doxycycline-inducible WAF1/Cip1 expression system in two glioblastoma cell lines and examined the role of WAF1/Cip1 in their response to the chemotherapy agents 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cis-diamminedichloroplatinum (cisplatin), in an isogeneic background. Our results showed that the induction of WAF1/Cip1 expression rendered glioma cells resistant to cell death induced by BCNU and cisplatin. Using an in vivo host-cell reactivation DNA repair assay, we demonstrated that WAF1/Cip1 enhances the repair of BCNU-induced DNA damage. We conclude that WAF1/Cip1 allows repair of BCNU- and cisplatin-damaged DNA and protects glioma cells from chemotherapy agent-induced apoptosis. Thus, blocking WAF1/Cip1 production or function may serve as a useful chemosensitization regimen for glioma.
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PMID:Overexpressed WAF1/Cip1 renders glioblastoma cells resistant to chemotherapy agents 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin. 953 61


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