Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Temozolomide (Temodal, Temodar), an imidazol derivative, is a second-generation alkylating agent. The orally available prodrug with the capacity of crossing the blood-brain barrier received accelerated US FDA approval in 1999. Three pivotal Phase II trials showed modest activity in the treatment of recurrent anaplastic astrocytoma glioblastoma. In 2005, the FDA and the European Agency for the Evaluation of Medicinal Products approved temozolomide for use in newly diagnosed glioblastoma, in conjunction with radiotherapy, based on an European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Phase III trial. The adverse events associated with temozolomide are mild-to-moderate and generally predictable; the most serious are noncumulative and reversible myelosuppression and, in particular, thrombocytopenia, which occurs in less than 5% of patients. Continuous temozolomide administration is associated with profound CD4-selective lymphocytopenia. Molecular studies have suggested that the benefit of temozolomide chemotherapy is restricted to patients whose tumors have a methylated methylguanine methyltransferase gene promotor and are thus unable to repair some of the chemotherapy-induced DNA damage. Temozolomide is under investigation for other disease entities, in particular lower-grade glioma, brain metastases and melanoma.
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PMID:Temozolomide: a milestone in neuro-oncology and beyond? 1692 85

Glioblastoma multiforme is the most common primary brain tumor in adults. Until recently, the standard of care consisted of maximal surgical resection followed by external beam radiotherapy. The role of adjuvant chemotherapy for newly diagnosed glioblastoma has been controversial; most of the numerous randomized phase III trials conducted over the past 40 years have failed to show a statistically significant and clinically meaningful survival advantage for patients randomized to the chemotherapy arm. Consequently, the choices of chemotherapeutics for patients with glioblastoma have been limited, and cytotoxic treatment regimens have usually included a nitrosourea. Temozolomide, a relatively new orally administered methylating agent, has demonstrable activity in glioma. A recent trial conducted under the auspices of the European Organization for the Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has defined a role for temozolomide in the initial management of glioblastoma. A companion correlative tumor-biology study has identified epigenetic silencing of the promoter of the gene that encodes MGMT (O6-methylguanine-DNA methyltransferase) in tumor specimens as a strong and independent prognostic factor for survival among patients with a newly diagnosed glioblastoma, as well as a predictor of survival benefit from chemoradiotherapy with temozolomide. This review briefly summarizes the development of temozolomide as a therapy for patients with malignant brain tumors, emphasizing recent trials that have established a new standard of care for patients with glioblastoma and speculating on how these advances might influence future therapeutic investigations for malignant primary brain tumors.
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PMID:Drug Insight: temozolomide as a treatment for malignant glioma--impact of a recent trial. 1693 4

Although autophagy enhances cell survival in nutrient-deprived cells by increasing adenosine triphosphate (ATP) production, it remains unclear if autophagy functions similarly in cells treated with cytotoxic chemotherapy agents. To address this issue, we measured both the ability of DNA damaging agents (Temozolomide, and Etoposide) to induce an autophagy-dependent production of ATP, and the effects of modulation of autophagy on drug-induced cell death. Both drugs induced an autophagy-associated increase in ATP production in multiple glioma cell lines. The drug-induced ATP surge could not be blocked by glucose starvation, but could be blocked by preincubation with the autophagy inhibitor 3-methyladenine (3-MA), an siRNA targeting beclin 1, or the mitochondrial inhibitor oligomycin. Inhibition of autophagy-induced ATP production increased non-apoptotic cell death associated with micronucleation, while restoration of the 3-MA-inhibited ATP surge by addition of pyruvate suppressed cell death. These results show that DNA damaging agents induce an autophagy-associated ATP surge that protects cells and may contribute to drug resistance.
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PMID:DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. 1694 31

Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.
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PMID:Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line. 1698 51

Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity against high grade glioma. Interferon-beta (IFN-beta) is known to have antiproliferative and antiangiogenic activities. The aim of this study was to elucidate whether an antiglioma effect could be potentiated by the combination of TMZ and IFN-beta. In vitro, the combination of these drugs suppressed the proliferative and migratory activities, as well as enhance of the apoptosis and cell cycle (S phase) arrest of U-87 cells more efficiently than TMZ or IFN-beta alone. IFN-beta exerted a potent inhibitory effect on the proliferation of human umbilical vein endothelial cells (HUVEC); however, no additive or synergistic effect was observed with the addition of TMZ. To determine in vivo effect, nude mice bearing intracerebral U-87 xenograft inoculation were treated with intraperitoneal administration of PBS, TMZ (15 mg/kg for 3 days), IFN-beta (2x10(5) IU for 15 days), and a TMZ + IFN-beta combination. The combined treatment (median 62.0+/-8.6 days, P=0.0005) was observed to significantly increase the survival of the animals compared to treatment with PBS (median 30.0+/-2.5 days), TMZ (median 41.0+/-3.5 days) or IFN-beta (mean 36.0+/-2.5 days). These results suggest that antiglioma activity can be enhanced by the combination of TMZ and IFN-beta, providing the possibility for a new strategy development in the management of malignant glioma.
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PMID:Potentiation of antiglioma effect with combined temozolomide and interferon-beta. 1708 46

The chemotherapeutic agent temozolomide produces O(6)-methylguanine (O6MG) in DNA, which triggers futile DNA mismatch repair, DNA double-strand breaks (DSB), G(2) arrest, and ultimately cell death. Because the protein complex consisting of Mre11/Rad50/Nbs1 (MRN complex) plays a key role in DNA damage detection and signaling, we asked if this complex also played a role in the cellular response to temozolomide. Temozolomide exposure triggered the assembly of MRN complex into chromatin-associated nuclear foci. MRN foci formed significantly earlier than gamma-H2AX and 53BP1 foci that assembled in response to temozolomide-induced DNA DSBs. MRN foci formation was suppressed in cells that incurred lower levels of temozolomide-induced O6MG lesions and/or had decreased mismatch repair capabilities, suggesting that the MRN foci formed not in response to temozolomide-induced DSB but rather in response to mismatch repair processing of mispaired temozolomide-induced O6MG lesions. Consistent with this idea, the MRN foci colocalized with those of proliferating cell nuclear antigen (a component of the mismatch repair complex), and the MRN complex component Nbs1 coimmunoprecipitated with the mismatch repair protein Mlh1 specifically in response to temozolomide treatment. Furthermore, small inhibitory RNA-mediated suppression of Mre11 levels decreased temozolomide-induced G(2) arrest and cytotoxicity in a manner comparable to that achieved by suppression of mismatch repair. These data show that temozolomide-induced O6MG lesions, acted upon by the mismatch repair system, drive formation of the MRN complex foci and the interaction of this complex with the mismatch repair machinery. The MRN complex in turn contributes to the control of temozolomide-induced G(2) arrest and cytotoxicity, and as such is an additional determining factor in glioma sensitivity to DNA methylating chemotherapeutic drugs such as temozolomide.
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PMID:The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity. 1712 22

The current standard of care for malignant gliomas is surgical resection and radiotherapy followed by extended adjuvant treatment with the alkylating agent temozolomide. Temozolomide causes DNA damage, which induces cell death. Through changes in the DNA-repair machinery, glioma cells develop resistance to temozolomide, compromising the therapeutic effect of the drug. Oncolytic viruses, such as herpes simplex viruses and adenoviruses, are being introduced into clinical trials as a new treatment for this malignancy. Biological studies have revealed that these viruses use mechanisms to either inactivate (adenovirus) or take advantage of (herpes simplex virus) the cellular DNA-repair machinery to achieve productive replication. Adenoviruses express proteins from the early genes to either downregulate the damage-repair enzyme, O(6)-methylguanine-DNA methyltransferase, or degrade poly (ADP-ribose) polymerase or the Mre11-Rad50-NBS1 complex, which detects DNA strand breaks. Temozolomide enhances herpes simplex virus oncolysis by upregulating the DNA repair-related genes growth arrest DNA damage 34 and ribonucleotide reductase. The interactions between viruses and the DNA-repair machinery suggest that a combined temozolomide and viral therapy will overcome the limitations of a single therapy by diminishing chemoresistance or enhancing oncolysis. This hypothesis has been supported by promising findings from preclinical and clinical studies.
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PMID:Oncolytic viruses and DNA-repair machinery: overcoming chemoresistance of gliomas. 1713 63

Temozolomide (TMZ) has demonstrated activity and acceptable toxicity for the treatment of recurrent malignant gliomas in carious prospective phase II studies. No information is, however, available on TMZ treatment for recurrent malignant glioma in Japanese patients. We report Hokkaido University Hospital experience on 35 adult patients with a recurrent malignant glioma, including 13 glioblastomas, 9 anaplastic astrocytomas, and 13 anaplastic oligondendroglial tumors. The median age was 52 years. The starting dose of TMZ was 150 mg/m2/day for 5 days. When no remarkable toxicity was observed, the dose was increased to 200 mg/m2 for subsequent cycles, every 4 week. In the 35 patients, the overall objective response rate (partial response) was 12% and 74% of the patients achieved disease stabilization. The median progression-free survival was 28 weeks and the median overall survival was 43 weeks. Although hematological toxicity was the most frequent adverse event (CTC grade 3 or 4 in 6 patients), overall toxicity was generally mild. Four patients required hospitalization due to the toxicity, but 28 patients had been treated with TMZ at our outpatient clinic. These results suggested that the reported efficacy and toxicity profile of TMZ for the treatment of Japanese patients with recurrent malignant glioma is reproducible from the setting of clinical trials in the western countries.
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PMID:[Temozolomide in the treatment of recurrent malignant glioma]. 1715 70

The prognosis for patients with malignant brain tumors has always been poor and until recently chemotherapy had not shown to be very effective. Temozolomide is a novel second-generation alkylating agent that has shown efficacy for the treatment of high-grade gliomas. Temozolomide is well-tolerated by most patients and has favorable pharmacodynamic and pharmacokinetic properties. In patients with newly diagnosed glioblastoma multiforme, radiation therapy with concurrent and adjuvant temozolomide significantly improves overall survival compared to treatment with only radiation. The benefit of temozolomide is greatest in patients with tumors that have a methylated 06-methyl-guanine DNA methyl transferase gene promoter that results in decreased repair of temozolomide-induced DNA damage. This chapter will briefly review the diagnosis and treatment of patients with malignant brain tumors and then will focus on the role of temozolomide in glioma therapy.
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PMID:[Glioma therapy up-date]. 1736 54

The alkylating agent temozolomide, commonly used in the treatment of malignant glioma, causes cellular cytotoxicity by forming O(6)-methylguanine adducts. In this report, we investigated whether temozolomide alters the activity of the transcription factor nuclear factor-kappaB (NF-kappaB). Temozolomide inhibits basal and tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB transcriptional activity without altering phosphorylation or degradation of inhibitor of kappaB-alpha. Inhibition of NF-kappaB is secondary to attenuation of p65 DNA binding, not nuclear translocation. Inhibition of DNA binding is shown both in vitro, with gel shift studies and DNA binding assays, and in vivo at kappaB sites. Consistent with inhibition of NF-kappaB activity, temozolomide reduces basal and TNFalpha-induced kappaB-dependent gene expression. Temozolomide also inhibits NF-kappaB activated by inducers other than TNFalpha, including lipopolysaccharide, doxorubicin, and phorbol 12-myristate 13-acetate. The inhibitory action of temozolomide on NF-kappaB is observed to be maximal following pretreatment of cells with temozolomide for 16 h and is also seen with the S(N)1-type methylating agent methylnitrosourea. The ability of temozolomide to form O(6)-methylguanine adducts is important for inhibition of NF-kappaB as is the presence of a functioning mismatch repair system. Activation of NF-kappaB with TNFalpha before administration of temozolomide reduces the cytotoxicity of temozolomide, whereas 16-h pretreatment with temozolomide resensitizes cells to killing. This work shows a mechanism whereby O(6)-methylguanine adducts formed by temozolomide lead to inhibition of NF-kappaB activity and illustrates a link between mismatch repair processing of alkylator-induced DNA damage and cell death.
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PMID:Inhibition of nuclear factor-kappaB activity by temozolomide involves O6-methylguanine induced inhibition of p65 DNA binding. 1763


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