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)

Malignant melanomas are highly resistant to chemotherapy. First-line chemotherapeutics used in melanoma therapy are the methylating agents dacarbazine (DTIC) and temozolomide (TMZ) and the chloroethylating agents BCNU and fotemustine. Here, we determined the mode of cell death in 11 melanoma cell lines upon exposure to TMZ and fotemustine. We show for the first time that TMZ induces apoptosis in melanoma cells, using therapeutic doses. For both TMZ and fotemustine apoptosis is the dominant mode of cell death. The contribution of necrosis to total cell death varied between 10 and 40%. The O(6)-methylguanine-DNA methyltransferase (MGMT) activity in the cell lines was between 0 and 1100 fmol mg(-1) protein, and there was a correlation between MGMT activity and the level of resistance to TMZ and fotemustine. MGMT inactivation by O(6)-benzylguanine sensitized all melanoma cell lines expressing MGMT to TMZ and fotemustine-induced apoptosis, and MGMT transfection attenuated the apoptotic response. This supports that O(6)-alkylguanines are critical lesions involved in the initiation of programmed melanoma cell death. One of the cell lines (MZ7), derived from a patient subjected to DTIC therapy, exhibited a high level of resistance to TMZ without expressing MGMT. This was related to an impaired expression of MSH2 and MSH6. The cells were not cross-resistant to fotemustine. Although these data indicate that methylating drug resistance of melanoma cells can be acquired by down-regulation of mismatch repair, a correlation between MSH2 and MSH6 expression in the different lines and TMZ sensitivity was not found. Apoptosis in melanoma cells induced by TMZ and fotemustine was accompanied by double-strand break (DSB) formation (as determined by H2AX phosphorylation) and caspase-3 and -7 activation as well as PARP cleavage. For TMZ, DSBs correlated significantly with the apoptotic response, whereas for fotemustine a correlation was not found. Melanoma lines expressing p53 wild-type were more resistant to TMZ and fotemustine than p53 mutant melanoma lines, which is in marked contrast to previous data reported for glioma cells treated with TMZ. Overall, the findings are in line with the model that in melanoma cells TMZ-induced O(6)-methylguanine triggers the apoptotic (and necrotic) pathway through DSBs, whereas for chloroethylating agents apoptosis is triggered in a more complex manner.
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PMID:Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53. 1912 57

A benefit of temozolomide (TMZ) is that myelotoxicity is uncommon. Recently, several small series have reported significant myelotoxicity resulting in treatment delays or death. The ability to predict risk of myelotoxicity may influence patient care. We retrospectively reviewed 680 malignant glioma patients and developed a clinical risk formula for myelotoxicity for each gender by logistic regression. The variables that remained were assigned a score of 1 and added together for a final risk score. Women experienced more myelotoxicity than did men (p = 0.015). For males, risk factors included body surface area (BSA) > or = 2 m(2) (odds ratio [OR] = 2.712, p = 0.04), not on steroids (OR = 2.214, p = 0.06), and on bowel medication (OR = 3.955, p = 0.008). For females, final factors included no prior chemotherapy (OR = 3.727, p = 0.001), creatinine > or = 1 mg/dl (OR = 6.08, p = 0.002), platelets < 270,000/mm(3) (OR = 2.438, p = 0.03), BSA < 2 m(2) (OR = 4.178, p = 0.04), not on medication for gastroesophageal reflux disease (OR = 2.942, p = 0.01), and on analgesics (OR = 2.169, p = 0.05). Age was included because of observable trends. Risk of developing myelotoxicity ranged from 0% to 33% (male) and from 0% to 100% (females). Polymorphisms in NQO1 (NAD(P)H dehydrogenase, quinone 1), MGMT (O(6)-methylguanine-DNA methyltransferase), and GSTP1 (glutathione S-transferase pi 1) were related to risk of developing myelotoxicity in a subset of patients. Myelotoxicity with TMZ is a significant clinical issue for those at risk. Use of a clinical model to predict risk and evaluation of identified genetic polymorphisms related to myelotoxicity may allow for individualized dosing, optimizing patient management.
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PMID:Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. 1917 23

Both DNA repair (MGMT) and immortalisation (telomerase) have been linked to the root of cancer. In glioma, MGMT expression is negatively regulated through promoter methylation and its absence is associated with enhanced chemosensitivity. However, recent studies indicate that telomerase is positively regulated through methylation and its elimination enhances chemotherapy. These observations suggest that suppression of telomerase in combination with MGMT may have additional anti-proliferative and anti-apoptotic effects, which may lead to increased patient survival rates. However, different approaches may be required to compliment the epigenetic events that regulate these genes. Nevertheless, given that median survival of glioma patients is less than a year, this review focuses on the recent approaches used to target MGMT and telomerase, with a view to increase life expectancy of patients while limiting side effects.
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PMID:Telomerase and DNA repair in glioma. 1923 90

The authors review the current literature on the major biological advances in the molecular testing of brain tumors. The incorporation of several new aspects required for proper disease management into traditional pathology service is the focus of this review. One of the important achievements of the last years in neuro-oncology is the observation that the promoter methylation status of the MGMT (O6-methylguanine DNA methyltransferase) gene determines the treatment efficacy of temozolomide (Temodal) in glioblastomas. This can best be evaluated by methylation-specific PCR (MSP) using tumor tissue obtained for histological evaluation. Furthermore, up-regulation of EGFR signaling through gene amplification has been recognized and targeted by anti-EGFR approaches in high-grade gliomas. The EGFRvIII mutant receptor is practically unique to glioma cells hence analysis of EGFR seems to be justifiably demanded either by oncologists or patients. Immunohistochemistry (IHC) can easily be included in routine laboratory workflow. In addition to this FISH analysis can be performed for the assessment of EGFR gene copy numbers at cellular level. Studying the EGFR status at a genetic and simultaneously at the protein expression level seems to be a valid approach for making treatment decision. Similarly complex and even less clear biological background characterizes the behavior of tumors with oligodendroglial differentiation. The deletion of the chromosomal regions 1p and 19q was found to be associated with favorable outcome and good response to the PCV treatment protocol. Therapeutic decisions are therefore also enabled on the basis of the 1p/19q status. Concurrent temozolomide/radiation therapy is often indicated on the basis of 1p/19q testing. The 1p/19q status can be assessed by FISH or, less frequently, by aCGH or LOH assay. Based on the in-depth overview of the literature the authors highly recommend the adaptation of molecular glioma testing that most efficiently could be done in centralized neuropathology laboratories. This approach would comply with the increasing need for personalized ("tailored") therapy while best satisfying cost/benefit issues.
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PMID:[Predictive molecular pathological testing in the diagnosis of high-grade tumors of glial origin]. 1931 24

Radiation therapy is a main pillar in the multimodal treatment of gliomas. However, application of radiation has to be adapted to the distinct characteristics of the various glioma subtypes, with respect to dosing, time-point of irradiation, choice of treatment technique, and more recently, of radiation quality.Treatment of low-grade gliomas has been characterized by much controversy, which is still ongoing. For anaplastic gliomas, addition of chemotherapy to radiation alone is currently being discussed and is evaluated in prospective trials. For glioblastomas, a change in treatment paradigm has taken place with the alkylating agent temozolomide, which could increase survival significantly for the first time in many centuries. Moreover, the first steps toward pretreatment stratification have been established by defining the role of MGMT-promotor methylation for treatment response and outcome.Over the last few years, particle therapy with protons and carbon ions has become available. These new radiation qualities now offer promising treatment alternatives that will be evaluated within clinical studies in the near future and have the potential to further improve outcome in patients with gliomas.
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PMID:Radiation therapy. 1932 41

Epigenetic gene regulation of specific genes strongly affects clinical outcome of malignant glioma. MGMT is the best studied gene for the connection of promoter methylation and clinical course in glioblastoma. While MGMT promoter methylation analysis currently does not alter treatment of glioblastoma patients, mainly because of a lack of convincing therapy to radiotherapy and concomitant administration of alkylating drugs, there is increasing interest on the part of patients and physicians in having this molecular parameter assessed. This chapter gives a short overview of the physiological characteristics of the epigenome in normal cells and tissues and the changes in epigenetic gene regulation following malignant transformation. It discusses the technical aspects, advantages, and shortcomings of currently used approaches for single-gene and genome-wide methylation analyses. Finally, an outlook is given on potential therapeutic avenues and targets to overcome tumor-suppressor gene silencing by aberrant promoter methylation in gliomas.
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PMID:Gene regulation by methylation. 1932 47

Gliomas are the most common primary human brain tumors. They comprise a heterogeneous group of benign and malignant neoplasms that are histologically classified according to the World Health Organization (WHO) classification of tumors of the nervous system. Over the past 20 years the cytogenetic and molecular genetic alterations associated with glioma formation and progression have been intensely studied and genetic profiles as additional aids to the definition of brain tumors have been incorporated in the WHO classification. In fact, first steps have been undertaken in supplementing classical histopathological diagnosis by the use of molecular tests, such as MGMT promoter hypermethylation in glioblastomas or detection of losses of chromosome arms 1p and 19q in oligodendroglial tumors. The tremendous progress that has been made in the use of array-based profiling techniques will likely contribute to a further molecular refinement of glioma classification and lead to the identification of glioma core pathways that can be specifically targeted by more individualized glioma therapies.
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PMID:Molecular neuropathology of gliomas. 1933 41

The incidence of gliomas is increasing worldwide, including India. Of the 18,820 new cases of primary central nervous system (CNS) tumors diagnosed annually in the United States, gliomas account for over 60% with 30-40% of them being glioblastoma multiforme (GBM), 10% being anaplastic astrocytoma (AA), and 10% being low grade gliomas (LGGs). This is in contrast to one study from West Bengal, India, in which only 7.9% of the brain tumors were GBMs, while 46.8% were astrocytomas. Of all adult primary CNS tumors, GBM is the most common and the most malignant with about 7,000 to 8,000 new cases annually in the United States. Given poor outcomes, a number of treatment approaches have been investigated. Common to these approaches is the use of adjuvant radiation therapy, even as surgery alone, with or without chemotherapy, may be the mainstay for some lower grade and low-risk gliomas. Today, treatment typically involves external beam radiation, with concurrent and adjuvant chemotherapy for more aggressive histologies. Although gliomas are relatively uncommon, active research is ongoing. Results of landmark trials along with some of the recently published trials are presented. These trials and management strategies as well as evolving concepts are found by reviewing over 200 articles in the National Library Medical (NLM) database, PubMed, more than 60 of which are refrenced. Specifically, the database is searched using the following keywords, with various combinations: glioma, low-grade, anaplastic, astrocytoma, oligodendroglioma, oligoastrocytoma, glioblastoma multiforme, chemotherapy, radiation, new concepts, phase III, MGMT, CDX-110 (Celldex), temozolomide, 1p/19q deletion, and bevacizumab.
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PMID:Evidence-based adjuvant therapy for gliomas: current concepts and newer developments. 1934 43

Human interferon-beta (IFN-beta) is known to exhibit pleiotropic biological activities including antitumor effects. On the other hand, temozolomide (TMZ), an oral bioavailable alkylating agent with excellent tolerability, has demonstrated efficacy and has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. More recent studies have indicated that there might be favorable therapeutic interactions between IFN-beta and TMZ, although the therapeutic advantages of such a combination have not yet been fully explored. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of IFN-beta and TMZ. The antitumor effect of and cell sensitivity to IFN-beta and TMZ and the synergistic potential of IFN-beta and TMZ in combination were evaluated in six malignant glioma cell lines. Correlations among the MGMT methylation status, quantitative level of MGMT mRNA, MGMT protein expression and the antitumor effect of these agents were also evaluated, since one of the most prominent resistance mechanisms to TMZ involves the DNA repair protein MGMT. The cell growth inhibitory effects of IFN-beta and TMZ on all tumor cell lines were observed in a dose-dependent manner, and the human malignant glioma-derived cell lines differed in their sensitivity to TMZ. The MGMT status, including promoter hypermethylation, quantitative mRNA expression and protein expression, was strongly correlated with TMZ sensitivity. A synergistic cell growth inhibitory effect and down-regulated MGMT mRNA levels were significantly observed when a clinically achievable CNS dose of IFN-beta was combined with TMZ, as compared to treatment with IFN-beta or TMZ alone in TMZ-resistant T98G cells. Furthermore, significant amounts of endogenous IFN-beta protein were detected in TMZ-treated T98G cells by ELISA. These results suggest that the clinical therapeutic efficacy of TMZ might be improved by a combination with IFN-beta in malignant gliomas unmethylated at the MGMT gene. The data provide an experimental basis for future strategies in TMZ chemotherapy, although further studies are needed to determine the detailed role of combined IFN-beta and TMZ chemotherapy in increasing tumor sensitivity.
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PMID:Effect of IFN-beta on human glioma cell lines with temozolomide resistance. 1951 61

1,3,8-Trihydroxy-6-methylanthaquinone (emodin) is recognized as an antiproliferative compound. In the present study, however, we show that emodin has both toxic and survival effects in glioma cells and that the survival effects involve Mdr1a. Emodin inhibited the proliferation and induced apoptosis of C6 cells in a 12-h treatment, but C6 cells survived a 72-h drug treatment, indicating resistance to emodin. Emodin-induced apoptosis was reduced by inhibition of the expression and activation of apoptosis-associated proteins including p53, Bax, Bcl-2, Fas, and caspase-3. C6 cells could express antioxidant proteins (superoxide dismutase and catalase) to decrease reactive oxygen species-induced cytotoxicity of emodin and overexpress multidrug resistance genes (Mdr1a, MRP2, MRP3, and MRP6) to decrease the intracellular accumulation of emodin. Electrophoretic mobility shift analysis showed that emodin decreased nuclear factor kappaB (NF-kappaB) expression in 24 h of treatment, but in 48 h, emodin increased NF-kappaB activity. A confocal microscope showed that emodin induced NF-kappaB translocation from cytoplasm to nuclei. C6 cells would activate the mitogen-activated protein kinase survival pathway and express the DNA repair gene (MGMT) and associated proteins (PARP and XRCC1) to recover the cell activity. C6 cells also expressed GRP78 to decrease emodin-induced endoplasmic reticulum (ER) stress that would cause apoptosis in C6 cells, and GRP78 inhibited the expression of GADD153 to enhance the expression of Bcl-2 that could balance the ER- and mitochondria-induced apoptosis of C6 cells.
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PMID:Emodin has cytotoxic and protective effects in rat C6 glioma cells: roles of Mdr1a and nuclear factor kappaB in cell survival. 1954 30


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