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)

Temozolomide is an oral cytotoxic agent that has demonstrated its interest in high grade glioma tumors. This drug can be used either concomitantly with radiotherapy or as chemotherapy. The prognosis of relapsing medulloblastoma is poor and treatment is often difficult, especially after radiotherapy. Here, we report the use of temozolomide in an adult presenting relapsing medulloblastoma. An initial partial response was observed for this previously heavily treated patient. This observation suggests this drug may be useful in medulloblastoma, either as conventional chemotherapy or for use together with radiotherapy.
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PMID:Temozolomide treatment of an adult with a relapsing medulloblastoma. 1788 60

Glioblastoma multiforme (GBM) are among the most devastating neoplasms claiming the lives of patients within a median of 1 year after diagnosis. Treatment of GBM requires a multidisciplinary approach. Treatments include surgery, radiotherapy, chemotherapy and so on. Temozolomide (TMZ) has emerged as an active agent against malignant gliomas. On the basis of the work by the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada, concurrent radiotherapy and the oral alkylating agent TMZ followed by adjuvant TMZ has become the standard of care for patients with newly diagnosed GBM, although the methylation status of the O(6)-mehylguanine-DNA methyltransferase promoter is predictive for survival of GBM patients. Gliadel is a biodegradable polymer wafer impregnated with carmustine. Gliadel has been one of the few treatment modalities to demonstrate a statistical benefit in patients with malignant glioma. These new FDA approved drugs advanced the treatment of malignant glioma, but more progress is needed. Patients require improvements in chemotherapy, surgery, radiotherapy, molecular targeted therapy, immunotoxin using the convection-enhanced delivery and more.
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PMID:Management of glioblastoma. 1803 58

Astroblastoma is a historically traded microscopic diagnosis to denote a rare neuroepithelial tumor of uncertain nosology, involving a distinctive pattern of pseudorosette arrangement of neoplastic cells. While displaying some glial properties, the latter shall not - by definition - be either reducible to or part of any conventional glioma type. We report on clinicopathologic correlations in a case of astroblastoma involving an extensive rhabdoid phenotype of tumor cells. The male patient was operated on at the age of 53 and 59 years for a left parietal tumor measuring 5.8 cm in diameter at the first presentation. On magnetic resonance imaging and angiography, both the primary and its recurrence were discrete, highly vascularized, and contrast-enhancing. The second surgery was complemented with radiotherapy of 66 Gy, followed by chemotherapy with Temozolomide. Twelve years into clinical history, the patient has stable minimal residual disease at the age of 65. A review of pathology samples from both surgeries showed well-differentiated astroblastoma according to current standards, with an MIB-1 labeling index of 1% and 4%, respectively. Neither of the specimens involved cellular anaplasia, overt mitotic activity, microvascular proliferation, or palisading necrosis. Most tumor cells harbored paranuclear filamentous rhabdoid inclusions that were immunostained for vimentin and, in part, also for GFAP. No polyantigenic reactivity was observed. This example contributes another facet to the spectrum of the so-called composite rhabdoid tumors. Involving a low-grade parent neoplasm, it also further substantiates the incipient perception that the rhabdoid phenotype neither is a peculiar but nonspecific convergence point of anaplastic evolution, nor are such lesions indiscriminately bound for a relentless course.
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PMID:Astroblastoma with rhabdoid features and favorable long-term outcome: report of a case with a 12-year follow-up. 1828 55

Malignant gliomas of which glioblastomas represent the ultimate grade of malignancy are characterized by dismal prognoses because malignant glioma cells present both important proliferation and neoangiogenesis processes and can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management. Invasive malignant glioma cells show a decrease in their proliferation rates and a relative resistance to apoptosis (type I programmed cell death) as compared to the highly cellular centre of the tumour, and this may contribute to their resistance to conventional proapoptotic chemotherapy and radiotherapy. The multidisciplinary up to date treatment for glioblastoma patients combined maximal surgical removal of the tumor with postoperative radiotherapy and concomitant chemotherapy with temozolomide. Temozolomide is a proautophagic (type II programmed cell death) drug and can thus circumvent part of the glioblastoma resistance to apoptosis. Another way to potentially overcome apoptosis resistance is to decrease the migration of malignant glioma cells in the brain, which then should restore a level of sensitivity to proapoptotic drugs. The Na(+)/K(+)-ATPase or sodium pump is an ion transporter which in addition to exchanging cations, is also the ligand for cardenolides and is directly involved in the migration of cancer cells in general and of glioma cells in particular. We have shown that the alpha1 subunit of the sodium pump is highly expressed in glioma cells compared to normal brain tissues and we are the first to propose the alpha1 subunit of the sodium pump as a new target in the context of malignant glioma treatment. Using a novel cardenolide with unique structural features, which markedly inhibits sodium pump activity and binds to the alpha1 subunit, we have shown marked anti-proliferative and anti-migratory effects on human glioblastoma cells (and other cancer cell types). We have characterized at least partially the anti-cancer mechanism of action of the novel cardenolide. It is a ligand of the alpha1 subunit of the pump which impairs the proliferation and migration of glioblastoma cells by disorganizing the actin cytoskeleton and inducing severe autophagic process in glioblastoma cells. Collectively, these data suggests that the novel cardenolide is an attractive candidate for preclinical and clinical development, at least in the area of glioblastoma. This compound should reach phase I clinical trials in the summer of 2008.
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PMID:[The sodium pump could constitute a new target to combat glioblastomas]. 1839 Apr 7

A multicenter phase I clinical trial, namely, Integrated Japanese Multicenter Clinical Trial: A Phase I Study of Interferon-beta and Temozolomide for Glioma in Combination with Radiotherapy (INTEGRA Study), is being conducted for patients with high-grade glioma in order to evaluate the safety, feasibility and preliminary clinical effectiveness of the combination of interferon-beta and temozolomide. The primary endpoint is incidence of adverse events. The secondary endpoints are progression-free survival time and overall survival time. In addition, objective tumor response will be evaluated in a subpopulation of patients with the measurable disease. The reduction rate of tumor will be calculated according to Response Evaluation Criteria In Solid Tumors for measurable tumors as determined by magnetic resonance imaging. Subsequently, the overall response will be evaluated based on the results of measurable and non-measurable tumors. Ten newly diagnosed and 10 recurrent patients will be enrolled in this study.
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PMID:A multicenter phase I trial of interferon-beta and temozolomide combination therapy for high-grade gliomas (INTEGRA Study). 1884 25

Previously, we demonstrated that demethylation with 5-Aza-2'-deoxycytidine (5azadC) resulted in reduced levels of telomerase that led to telomere shortening, enhanced MGMT expression and enhanced chemosensitivity. Although the results were encouraging, the fact that 5azadC is highly toxic and nonspecific, thus is not favored as a therapeutic molecule. The aim of this research is to downregulate the DNA methyltransferase (DNMT1) gene using three sets of double-stranded RNA oligos designed to align different regions of DNMT1 sequence. Results showed the small-interfering RNA (siRNA) 1 and 3 demonstrated significant levels of silencing DNMT1 and hTERT transcription after 24-hour treatment (p = 0.01) and approximately 90% and 70% transcriptional downregulation of DNMT1 and hTERT, respectively after 48 hours. However, siRNA 2 downregulated DNMT1, hTERT, and MGMT in GOS-3 and U87-MG cells that was attributed to sequence homology between oligo 2 and MGMT complementary DNA. The siRNA-treated glioma cell lines GOS-3 and U87-MG were subjected to two chemotherapeutic agents; taxol and Temozolomide (TMZ). Results suggest that either a combination of siRNA 1 or 3 followed by taxol (2-6 muM) after 48 hours or a combination of siRNA 1 or 3 followed by TMZ (600-1000 microM) after 24 hours would be novel and effective glioma therapies.
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PMID:Silencing DNA methyltransferase (DNMT) enhances glioma chemosensitivity. 1892 31

The present study aims to assess the feasibility and the effectiveness of a second-line Fotemustine chemotherapy in patients with recurrent Glioblastoma after standard primary treatment. Between 2005 and 2007, 50 patients with relapsed malignant glioma (median age=56.8 years; median KPS=90) underwent a second-line chemotherapy with Fotemustine. Selected patients were previously treated with a standard 60 Gy Radiotherapy course and Temozolomide Chemotherapy. Patients were stratified into classes according to the prognostic Recursive Partition Analysis. Endpoints of the study were Progression Free Survival at 6 months, duration of Objective Response and Stabilization, Overall Survival and toxicity. At analysis, 36 patients were dead and 14 were alive. Median follow-up from primary diagnosis was 26.6 months. The Efficacy control of the disease was 62%. PFS was 6.1 months; PFS-6 was 52% and median overall survival from primary diagnosis was 24.5 months, with few manageable haematological toxicities. Fotemustine was safe and effective as second-line chemotherapy in recurrent glioblastoma.
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PMID:A multi-institutional phase II study on second-line Fotemustine chemotherapy in recurrent glioblastoma. 1901 76

Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period [Y. Hirose, M.S. Berger, R.O. Pieper, p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells, Cancer Res. 61 (2001) 1957-1963; W. Roos, M. Baumgartner, B. Kaina, Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1, Oncogene 23 (2004) 359-367]. Here we show that TMZ and BCNU have an earlier effect on nuclear organization and chromatin structure. In particular, we report that TMZ and BCNU induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1alpha bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. We conclude that TMZ and BCNU efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence.
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PMID:Temozolomide and carmustine cause large-scale heterochromatin reorganization in glioma cells. 1911 35

Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3-5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.
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PMID:Rechallenge with temozolomide in patients with recurrent gliomas. 1924 Sep 62

In normal brain, the side population (SP) phenotype is generated by ABC transporter activity and identifies stem cell and endothelial cell subpopulations by dye exclusion. By drug efflux, the ABCG2 transporter provides chemoresistance in stem cells and contributes to the blood brain barrier (BBB) when active in endothelial cells. We investigated the SP phenotype of mouse and human gliomas. In glioma endothelial cells, ABC transporter function is impaired, corresponding to disruption of the BBB in these tumors. By contrast, the SP phenotype is increased in nonendothelial cells that form neurospheres and are highly tumorigenic. In this cell population, Akt, but not its downstream target mTOR, regulates ABCG2 activity, and loss of PTEN increases the SP. This Akt-induced ABCG2 activation results from its transport to the plasma membrane. Temozolomide, the standard treatment of gliomas, although not an ABCG2 substrate, increases the SP in glioma cells, especially in cells missing PTEN.
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PMID:PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. 1926 52


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