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

The oral alkylating agent, temozolomide (Temodal: TMZ), is the only anticancer drug that has been shown in a phase III study to improve survival in glioblastoma (GBM) when administered with concomitant radiotherapy. Pharmacokinetic studies have documented relatively high concentrations of TMZ in brain tumors and cerebrospinal fluid (20-40% of the area under the plasma concentration curve), and other studies have demonstrated that TMZ is effective for treatment of various brain tumors, including recurrent and newly diagnosed glioma, primary CNS lymphoma, metastatic melanoma, and neuroblastoma. Molecular markers that predict a favorable response to TMZ plus concomitant radiotherapy include methylguanine methyltransferase (MGMT) promoter methylation patients with GBM and chromosome 1p/19q deletion in patients with anaplastic oligodendroglioma or low-grade glioma. Myelosuppression, nausea and constipation are relatively frequent in patients undergoing treatment with TMZ, and prophylaxis against Pneumocystis carinii pneumonia should be instituted. This article will summarize and discuss these issues as well as review ongoing and anticipated studies of TMZ in combination with other anti-cancer therapies.
 ...
PMID:[Temozolomide: Temodal]. 1834 14

Glioblastoma (GBM) is the most malignant among astrocytic tumours and is associated with a poor prognosis. Age, performance status, mini-mental status examination score, methylation status of methylguanine methyltransferase promoter and extent of surgery constitute the main prognostic factors. Surgery aimed to complete resection should be the first therapeutic modality in the management of glioblastoma. However, complete resection is virtually impossible due to infiltrative nature of this disease and relapse is almost inevitable. Postoperative concomitant chemo-radiation is the standard treatment and consists of 60Gy of external-beam radiotherapy (to be delivered to a target volume including a 2-3cm ring of tissue surrounding the perimeter of the contrast enhancing lesion on pre-operative CT/MRI scans) plus temozolomide (TMZ) administered concomitantly (75mg/m(2) daily) and after radiotherapy (150-200mg/m(2), for 5 days every 4 weeks). At time of recurrence/progression, a nitrosourea-based chemotherapy constitutes a reasonable option, as well as a temozolomide re-challenge for patients without progression during prior temozolomide treatment.
 ...
PMID:Glioblastoma in adults. 1839 16

The prognosis for patients with newly diagnosed malignant gliomas remains poor; however there have been some recent advances in treatment that have generated optimism. Medical management usually includes administration of corticosteroids to control peritumoral edema. Anticonvulsants are indicated for patients with established tumor-related seizures; however, the prophylactic use of anticonvulsants remains controversial. Advances in neurosurgical techniques have improved the safety of tumor resection and most patients undergo the maximal safe surgical debulking of tumor. The tissue sample obtained provides conclusive pathologic diagnosis and tumor classification and extensive tumor resection may impact patient outcome. For glioblastoma, external beam radiation had been the conventional first line treatment; however a recent international phase III trial has provided level 1 evidence that a chemoradiation regimen using external beam radiation plus the oral chemotherapy agent temozolomide provides a survival advantage over radiation alone. Correlative studies were also performed that demonstrated better outcomes for patients with tumors demonstrating methylation (inactivation) of the promoter region of methyl guanine methyltransferase (MGMT) gene. Additional studies are in progress building on the clinical trial results using different dosing schedules of temozolomide and combination regimens. Studies are also underway to develop molecular markers, such as expression of MGMT that may help select the patients most likely to benefit from this treatment.
 ...
PMID:Management of patients with newly diagnosed malignant primary brain tumors with a focus on the evolving role of temozolomide. 1851 57

True multicentric glioblastoma multiforme (GBM) is rare and consists of separate distinct tumors in different cerebral lobes or hemispheres without any apparent route of dissemination. Few data are available describing its imaging using positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D: -glucose (FDG). In this paper, we report on the case of a man with bifocal tumor in the right frontal and temporal lobes who underwent FDG-PET imaging. Visual and semiquantitative analysis showed two different metabolic patterns with much more intense uptake in the smaller temporal lesion. Subtotal surgical removal of the main frontal lesion allowed satisfactory control in the operative site, whereas the temporal lesion was rapidly progressive with occurrence of necrosis, which led to a second neurosurgery. The diagnosis of glioblastoma was confirmed by neuropathological examination in both cases but with much higher immunohistochemical expression of O(6)-methylguanine-DNA-methyltransferase (MGMT) in the temporal lesion. This report illustrates the potential interest of FDG-PET in multicentric GBMs to identify different metabolic patterns, in accordance with clinical, morphological, and molecular aggressiveness.
 ...
PMID:FDG-PET to predict different patterns of progression in multicentric glioblastoma: a case report. 1856 92

The DNA repair and detoxifying enzymes, O(6)-methylguanine-DNA-methyltransferase (MGMT) and glutathione-S-transferase (GST), may be responsible fpr poor response to alkylating agents in glioblastoma treatment. The methylation of MGMT promoter and the expression of MGMT and GST were highly heterogeneous in surgical specimens of human glioblastoma and in established human glioblastoma cells under 2-D and 3-D culture conditions, suggesting an intrinsic property of these cells. MGMT and GST expression did not predict the sensitivity of glioblastoma cells to alkylating agents. Combination of alkylating agents with inhibitors of GST disclosed additive effects, suggesting that inhibition of GST should be considered in glioblastoma therapy.
 ...
PMID:Heterogeneity of human glioblastoma: glutathione-S-transferase and methylguanine-methyltransferase. 1858 51

The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells (CSC) maintaining these tumors persist. We have therefore investigated the effect of temozolomide on CD133(+) and CD133(-) GBM CSC lines. Although differentiated tumor cells constituting the bulk of all tumor cells were resistant to the cytotoxic effects of the substance, temozolomide induced a dose- and time-dependent decline of the stem cell subpopulation. Incubation with sublethal concentrations of temozolomide for 2 days completely depleted clonogenic tumor cells in vitro and substantially reduced tumorigenicity in vivo. In O(6)-methylguanine-DNA-methyltransferase (MGMT)-expressing CSC lines, this effect occurred at 10-fold higher doses compared with MGMT-negative CSC lines. Thus, temozolomide concentrations that are reached in patients were only sufficient to completely eliminate CSC in vitro from MGMT-negative but not from MGMT-positive tumors. Accordingly, our data strongly suggest that optimized temozolomide-based chemotherapeutic protocols might substantially improve the elimination of GBM stem cells and consequently prolong the survival of patients.
 ...
PMID:Temozolomide preferentially depletes cancer stem cells in glioblastoma. 1962 70

At least 10% of glioblastoma relapses occur at distant and even contralateral locations. This disseminated growth limits surgical intervention and contributes to neurological morbidity. Preclinical data pointed toward a role for temozolomide (TMZ) in reducing radiotherapy-induced glioma cell invasiveness. Our objective was to develop and validate a new analysis tool of MRI data to examine the clinical recurrence pattern of glioblastomas. MRIcro software was used to map the location and extent of initial preoperative and recurrent tumors on MRI of 63 patients in the European Organisation for Research and Treatment of Cancer (EORTC) 26981/22981/National Cancer Institute of Canada (NCIC) CE.3 study into the same stereotaxic space. This allowed us to examine changes of site and distance between the initial and the recurrent tumor on the group level. Thirty of the 63 patients were treated using radiotherapy, while the other patients completed a radiotherapy-plus-TMZ treatment. Baseline characteristics (median age, KPS) and outcome data (progression-free survival, overall survival) of the patients included in this analysis resemble those of the general study cohort. The patient groups did not differ in the promoter methylation status of methyl guanine methyltransferase (MGMT). Overall frequency of distant recurrences was 20%. Analysis of recurrence patterns revealed no difference between the groups in the size of the recurrent tumor or in the differential effect on the distance of the recurrences from the preoperative tumor location. The data show the feasibility of groupwise recurrence pattern analysis. An effect of TMZ treatment on the recurrence pattern in the EORTC 26981/22981/NCIC CE.3 study could not be demonstrated.
 ...
PMID:A novel tool to analyze MRI recurrence patterns in glioblastoma. 1867 55

Resistance to alkylating agents via direct DNA repair by O(6)-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O(6)-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.
 ...
PMID:Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. 1875 34

Evidence from several studies supports that the epigenetic, transcriptional and translational regulation and expression of O6-methylguanine-methyltransferase (MGMT) is relevant for prognostic and predictive considerations in glioblastoma patients. MGMT status is being used as a stratifying factor or eligibility criterion in ongoing and accruing clinical glioblastoma trials. In some cases, there is also interest in MGMT assessment of glioblastoma tissue in the day-to-day clinical setting. However, a number of different methods and protocols have been used for MGMT analysis and it is unclear which methods harbour the greatest potential for translation into routine clinical use. This article reviews methods that have been used for MGMT assessment at DNA-, RNA- and protein-level in glioblastoma with a focus on their potential clinical utility. Conclusions. (1) DNA-based methods for MGMT analysis seem more promising for translation into the clinical setting than RNA- or protein-based methods. However, at present there is lack of data to base recommendations for a specific method or protocol for MGMT testing on. There is a strong need for systematic comparisons and validation of intra- and interlaboratory reproducibility and clinical performance of different methods for MGMT assessment to identify the best method for clinical MGMT testing. (2) The current practice of formalin-fixation of neurosurgical specimens considerably limits the spectrum of methods that can be applied for molecular diagnosis in clinical neuro-oncology. Further studies may be helpful to establish more appropriate protocols for tumour tissue preservation (e.g. identification of alternative fixatives that do not deteriorate DNA and RNA quality).
 ...
PMID:MGMT analysis at DNA, RNA and protein levels in glioblastoma tissue. 1922 54

Despite recent and significant progress, the prognosis of glioblastoma remains extremely poor. Concomitant chemoradiotherapy with temozolomide is now the standard of care for newly diagnosed glioblastoma. This treatment is well-tolerated and results in improvement of overall survival and dramatic increase of long term survivor rate, especially in good performance status patients. Besides, this benefit is particularly marked in patients with MGMT (methylguanine methyltransferase) methylated tumor, suggesting a growing place of molecular markers in pattern of care of such patients. At recurrence, the combination of bevacizumab (anti-VEGF) with irinotecan has shown surprising high response rates in a phase II trial for recurrent malignant gliomas. Many other targeted therapies are currently under investigation, alone or in association, at recurrence or up-front and during radiotherapy. For this reason, in the future a more precise understanding of gliomagenesis is needed for a better molecular stratification of patients.
 ...
PMID:[Association of radiotherapy and chemotherapy-targeted therapies in glioblastomas]. 1931 7


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>