Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report two patients with acute myeloid leukemia (AML) following therapy for malignant glioma; one was a young women treated heavily with alkylating agents for glioblastoma and the other a young man treated with high doses of procarbazine, lomustine, and vincristine (PCV) for anaplastic astrocytoma. We found 26 other examples of therapy related leukemia in adult and pediatric brain tumor patients. Including our two, there were 12 patients with malignant glioma; median interval from treatment to diagnosis of AML was 31 months. Nine adult malignant glioma patients all received nitrosoureas, some as the sole form of chemotherapy. No definite cases occurred after radiotherapy alone. Based upon analogy with other cancers, the cumulative dose of chemotherapy, especially alkylating agents, is the major risk factor for development of secondary AML. Agents implicated include carmustine (BCNU), lomustine (CCNU), and procarbazine. Conventional radiotherapy appears not to confer additional risk. Progressive macrocytosis, early dose reductions for thrombocytopenia, and refractory anemia may provide early diagnostic clues. Current glioma therapy is leukemogenic but the number of patients who survive the interval required to induce AML is small; nevertheless, the identification of chemosensitive types of glioma, and subgroups of patients who derive the most benefit from chemotherapy, may result in increasing numbers of patients at risk of long term complications. If regimens such as PCV continue to prove valuable in neurooncology the risk of leukemia will require integration into the clinical decision process. A search for more effective therapy with minimal mutagenicity remains critical.
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PMID:Acute leukemia following treatment of malignant glioma. 987 84

The aim of this retrospective study was to evaluate the effect of adjuvant chemotherapy among patients < 55 years of age with anaplastic gliomas (historical grade 3, n = 85) with four cycles 4 weeks apart of 160 mg carmustine (BCNU) infused into the internal carotid artery, combined with vincristine 2 mg and procarbazine 50 mg x 3 for 1 week (i.a.BCNU-PV) versus no adjuvant chemotherapy. In glioblastomas (histological grade 4, n = 257) the same chemotherapy was evaluated versus two cycles 4 weeks apart of 160 mg lomustine (CCNU) orally instead of BCNU, combined with vincristine and procarbazine (PCV) versus no chemotherapy. All patients in both groups received radiotherapy. Among glioblastoma patients < 55 years of age there was a significant (P = 0.03), but moderately increased survival in the i.a.BCNU-PV group versus the two other arms that did not differ from each other. This difference could be explained by an uneven distribution of prognostic factors, especially age group (< 50 years versus 50-54 years) in favour of the i.a.BCNU-PV group. In anaplastic gliomas, the median survival in the i.a.BCNU-PV group was 80 months versus 25 months for the no chemotherapy arm (P = 0.004). No significant differences in the distribution of prognostic factors were found between the two therapy arms. We suggest that the role of adjuvant chemotherapy in glioblastomas is unclear, while i.a.BCNU-PV as adjuvant chemotherapy among patients < 55 years of age and with anaplastic gliomas increased survival markedly.
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PMID:A retrospective study of the value of chemotherapy as adjuvant therapy to surgery and radiotherapy in grade 3 and 4 gliomas. 989 29

The effectiveness of chemotherapy for human cancers is limited by pharmacokinetic parameters such as variation in metabolism and is determined by the cellular response. In this work, we aimed to gain a more holistic understanding of the molecular basis of glioma response to the DNA-alkylating agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by using a systematic approach: we investigated the expression of 588 genes with various cellular functions in a BCNU-resistant glioblastoma cell line and a BCNU-sensitive subline before and after treatment with BCNU. Our gene expression profiling revealed major differences in gene expression between these two cell lines, especially after treatment with BCNU. One striking example was that BCNU decreased the expression of six DNA-repair genes in sensitive but not in resistant cells. In sensitive cells, BCNU treatment resulted in the induction of two MAP kinase genes; this finding suggests that the specific response to BCNU in sensitive cells may involve the Jun kinase signal transduction pathway. After BCNU treatment, marked induction of tumor necrosis factor was detected only in sensitive cells, suggesting that tumor necrosis factor is a mediator of BCNU-induced cell death. Bcl-2 family members were not altered by BCNU in sensitive cells, suggesting that BCNU-induced cell death may be independent of the bcl-2 pathway. Results of the present study demonstrate that gene expression profiling may facilitate identification of cellular pathways associated with specific responses to chemotherapeutic agents and contribute to an understanding of the molecular basis of drug action.
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PMID:Characterization of cellular pathways involved in glioblastoma response to the chemotherapeutic agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) by gene expression profiling. 1002 10

We investigated the efficacy of 3 different systemic chemotherapy regimes in 122 patients with histologically confirmed glioblastoma, KPS > 60, age < 65. Locoregional chemotherapy was delivered to 22 patients from all three systemic chemotherapy groups. Chemotherapy was given before and during radiotherapy, which was the same for all patients consisting of unconventional fractionation with a break between courses. Survival (Kaplan-Meier) was significantly longer in the subgroup receiving cisplatinum plus BCNU compared to those receiving cisplatinum plus etoposide or carboplatinum plus BCNU with median survival time 21.5 months, 15 months and 15 months respectively (log rank test p = 0.01). Survival was also significantly longer in patients who received locoregional therapy compared to those who received only systemic chemotherapy (21 vs 15 months, p = 0.01). Univariate analysis showed that age, postoperative Karnofsky status and extent of resection were not predictive of survival in the series, although there were trends to better outcome in younger patients and those undergoing total/subtotal resection. Age, systemic chemotherapy type and interstitial treatment were included in a multivariate analysis, and both locoregional treatment and chemotherapy with cisplatinum plus BCNU were significantly predictive of survival [P = 0.01]. These encouraging preliminary results suggest that further trials with locoregional and systemic therapy prior to radiotherapy are worth pursuing.
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PMID:Interstitial chemotherapy plus systemic chemotherapy for glioblastoma patients: improved survival in sequential studies. 1022 35

In this article, we investigated the effect induced by the reintroduction of wild-type p53 (wt-p53) protein on BCNU sensitivity in the ADF glioblastoma line. Using a wt-p53 recombinant adenovirus (Ad-p53), we demonstrated that exogenous wt-p53 expression was able to increase the sensitivity to BCNU in ADF cells. Interestingly, this effect was more evident when Ad-p53 infection was performed after BCNU treatment compared with the opposite sequence. To understand the biological basis of these different behaviors, we analyzed the cell cycle of the differently treated cells. We found that Ad-p53 infection induced a persistent accumulation of cells in the G0/G1 phase while, as expected, BCNU induced a block in the G2-M phase. Ad-p53-->BCNU sequence did not significantly modify the cell cycle profile in respect of Ad-p53 infected cells. In contrast, BCNU-->Ad-p53 sequence provoked G2-M arrest similar to that observed after treatment with BCNU alone, but prevented the later recovery of the cells through the cell cycle, by driving the cells to apoptotic death. These results demonstrate that the administration sequence is important to increase drug sensitivity. To generalize the phenomenon observed on ADF line, the antiproliferative effect of the two different schedules was analyzed on other glioblastoma lines (A172, CRS-A2, U373MG) with different BCNU sensitivity and p53 status. The data obtained confirm that the wt-p53 gene transfer enhances BCNU sensitivity in glioblastoma cells depending on the administration sequence.
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PMID:Increase of BCNU sensitivity by wt-p53 gene therapy in glioblastoma lines depends on the administration schedule. 1045 9

We investigated the potential mechanisms of tamoxifen cytotoxicity in the U-373, U-138, and U-87 human glioblastoma cell lines, namely interference with protein kinase C (PKC) activity, the oestrogen receptor, and/or the production of transforming growth factor beta 1 (TGF-beta 1). We further examined the effects of tamoxifen on the cytotoxicity exerted by gamma-radiation, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and etoposide in this cell line panel. Thus, the cells were treated for 4 days with tamoxifen, gamma-radiation, purified recombinant human TGF-beta 1 (rhTGF-beta 1), BCNU, or etoposide, either alone or at certain combinations. Cellular responses were evaluated with the sulphorhodamine B assay, as well as by multiple drug effect analysis, and related to PKC activities in particulate and cellular fractions; cellular oestrogen receptor contents; and the influence of rhTGF-beta 1 on cell growth. Tamoxifen inhibited cell proliferation as well as the phosphorylation capacity of the particulate, but not of the cytosolic fractions dose-dependently, at comparable kinetics, and at IC50 values of approximately 15 microM. At these concentrations, tamoxifen acted synergistically with gamma-radiation (4- to 6-fold) and additively with BCNU (approximately 2-fold), but did not affect etoposide cytotoxicity. The cells were negative to immunostaining for the oestrogen receptor, and rhRGF-beta 1 did not influence their growth up to 100 nm. Our data suggest that tamoxifen can sensitise cultured glioblastoma cells not to etoposide but to gamma-radiation and BCNU, possibly through interference with membrane PKC, supporting its evaluation in experimental protocols for primary malignant gliomas.
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PMID:Tamoxifen inhibits particulate-associated protein kinase C activity, and sensitises cultured human glioblastoma cells not to etoposide but to gamma-radiation and BCNU. 1050 46

We sought to characterize the effects of radiation alone and in combination with BCNU and dexamethasone on malignant glioma invasion. A model of malignant glioma invasion into a gel matrix of collagen type I was used to characterize response to radiation treatment for four malignant glioma cell lines (C6, U251, U373, A172) and nine primary human glioblastoma explants. A radiation dose dependent inhibition of invasion was noted for the C6 astrocytoma cell line but not the other cell lines or explants. Addition of BCNU and dexamethasone to radiation produced additional inhibition of invasion among the cell lines and explants but could not suppress invasion entirely.
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PMID:Effects of radiation on a model of malignant glioma invasion. 1072 Feb 2

Human malignant gliomas are commonly resistant to chemotherapy. Here, we examined the role of the multidrug resistance (mdr) mechanism in the chemo-resistance of these tumors, using a twofold approach: (i) by assessing a possible mdr phenotype before and after chronic drug exposure of glioma cells in vitro, and (ii) by assessing the modulation of expression of the mdr-associated P-glycoprotein (Pgp) using radiotherapy and serial cycles of chemotherapy in human glioblastoma patients in vivo. T98G, and to a lesser degree, LN-229 human malignant glioma cells exhibit a constitutive mdr phenotype as determined by the modulation of dye transport and by the augmentation of chemosensitivity by the mdr antagonist, verapamil. Thus, coexposure to verapamil enhances the cytotoxicity of vincristine, doxorubicin and VM26 in T98G cells and that of vincristine in LN-229 cells. Chronic exposure of the cells to low concentrations of vincristine and doxorubicin, but not VM26, topotecan or BCNU, moderately enhances the mdr-like phenotype, as assessed by drug expulsion assays. However, chronic exposure to increasing drug concentrations does not significantly alter the sensitivity to the respective drugs. These data are consistent with a constitutive, but not drug-inducible, mdr-like drug resistance in glioma cells in vitro. Immunocytochemical analysis of human malignant gliomas in vivo reveals that Pgp expression is more abundant in endothelial cells within the gliomas, than in the glioma cells proper. Importantly, Pgp expression is unaltered by radiochemotherapy, assessed by comparative immunocytochemistry of glioma specimens obtained serially before and after radiochemotherapy. We conclude that (i) glioma cells exhibit constitutive mdr-like drug resistance that is not significantly altered by chronic drug exposure in vitro; (ii) endothelial cells may play an important role in Pgp-mediated drug resistance of gliomas in vivo; (iii) radiotherapy and repeated chemotherapy cycles do not modulate Pgp expression in human malignant gliomas in vivo; (iv) there is preliminary evidence for a non-Pgp, verapamil-sensitive drug transport activity in glioma cells.
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PMID:Evidence for a constitutive, verapamil-sensitive, non-P-glycoprotein multidrug resistance phenotype in malignant glioma that is unaltered by radiochemotherapy in vivo. 1080 1

We treated 54 patients, newly diagnosed for glioblastoma, with systemic chemotherapy (carmustine (BCNU) 100 mg/m2 and cisplatin 90 mg/m2 every 6 weeks) and radiotherapy soon after surgery. In 10 cases the treatment was combined with locoregional chemotherapy (1 mg bleomycin on days 1-2, and 3 mg mitoxantrone on day 3, repeated every 20 days) administered from an Ommaya reservoir. At tumor recurrence, all patients were treated with procarbazine, lomustine and vincristine (PCV); 15 of 54 were reoperated and treated with locoregional chemotherapy. The median time to disease progression (TTP) and overall survival time (ST) for the whole group were 10.8 and 23.1 months, respectively. The ST of the 15 reoperated patients who also received locoregional treatment at disease recurrence was 27.6 months; this was significantly longer than that of patients not reoperated and not treated locally (log-rank p=0.04). The results in our reoperated subgroup support the opinion that a second operation could be suitable if it is part of the whole program of treatment.
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PMID:Locally delivered chemotherapy and repeated surgery can improve survival in glioblastoma patients. 1093 84

Bcl-2 protein plays an important role in inhibiting apoptosis and protecting normal and neoplastic cells from toxicity. Bcl-2 overexpression in malignant tumors, on the other hand, may cause resistance against adjuvant treatment. Since there are subpopulations of patients with glioma that differ considerably in their treatment benefit, it is important to identify prognostic factors for outcome and to tailor adjuvant protocols in accordance with specific biological features of the respective tumor. The present study aimed at investigating the role of bcl-2 expression in higher-grade glioma (WHO grade III and IV). Bcl-2 expression was correlated with clinical and paraclinical parameters, and evaluated in univariate and multivariate statistical models. In addition, bcl-2-overexpressing human glioma cells in culture were used for modeling the in vivo findings and for investigating the importance of bcl-2 for tumor resistance against cytotoxic treatment. A group of 86 patients with higher-grade glioma were investigated. Anaplastic astrocytoma (AA; WHO G III, n = 29) showed bcl-2 expression in 48% of the cases, and immunohistochemical positivity was associated with a significantly shorter survival time (p = 0.0068). In glioblastoma patients (GBM; WHO G IV, n = 57), 51% of tumors were bcl-2 positive, but bcl-2 expression did not correlate significantly with survival (p = 0.39). In a Cox proportional hazards regression model, bcl-2 positivity was confirmed as a negative prognostic parameter in AA, but not in GBM. Bcl-2 overexpressing and control human glioma cell clones (T98MG line) were treated in culture with the cytotoxic drugs carmustine (BCNU), paclitaxel, vincristine, and doxorubicin. In addition, bcl-2-overexpressing and control cells were infected with a retrovirus carrying the herpes-simplex-virus thymidine kinase gene (HSV-tk), and then treated with ganciclovir (GCV). Bcl-2 overexpression significantly increased tumor cell resistance against all of the above cytotoxic drugs, and also against HSV-TK/GCV mediated gene therapy.
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PMID:Bcl-2 expression in higher-grade human glioma: a clinical and experimental study. 1110 Aug 18


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