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diagnostics
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introduction of the MS-MLPA assay may not only be helpful for predicting response of gliomas to temozolomide, but may also facilitate tailor-made treatment with other chemotherapeutic agents for a variety of tumors
drug development
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highly effective inactivation of MGMT by an oligodeoxyribonucleotide containing O6-(4-bromothenyl)guanine suggests that such oligodeoxyribonucleotides might have therapeutic applications if problems of delivery can be addressed
molecular biology
modest binding cooperativity and high binding densities of AGT are adaptations that allow the enzyme to efficiently search for lesions in the context of chromatin remodeling and DNA replication
analysis
ability to specifically label AGT fusion proteins in the presence of endogenous AGT, after brief incubation of the cells with a small-molecule inhibitor, may significantly broaden the scope of application of AGT fusion proteins for studying protein function in living cells
analysis
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N-terminal domain plays a critical structural role in maintaining an active configuration of the C-terminal domain, N-hAGT and C-hAGT domains can protect from N-methyl-N'-nitro-N-nitrosoguanidine in Escherichia coli GWR-109 cells
analysis
overexpression of human MGMT provides protection against the toxic effects of N-methyl-N'-nitro-N-nitrosoguanidine
analysis
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strategy of loop insertion to alter enzyme specificity shall be general and applicable to other classes of proteins, the isolated AGT mutant can be applied in molecular imaging, where the mutant and parental AGTs are used to label two different AGT fusion proteins with different fluorophores in the same living cell or in vitro, allows establishment of fluorescence-based assays to detect protein-protein interactions and measure enzymatic activities
medicine
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the enzyme is important in cellular resistance to certain alkylating antitumor agents such as the methylating drug temozolomide. Cisplatin is able to decrease enzyme levels in Jurkat cells, probably via the inhibition of gene transcription. The clinical efficiacy of triazene compounds might be improved by combination with cisplatin using appropriate doses and schedules of administration
medicine
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high level of enzyme in tumors and relative resistance to cyclophosphamide in lung cancer indicates that 6-O-methylguanine-DNA methyltransferase may be a predictive factor of resistance to cyclophosphamide
medicine
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the efficiacy of 6-O-benzylguanine as a chemomodulator depends on the extent of depletion of 6-O-methylguanine DNA methyltransferase in normal tissues and the optimal therapeutic index for combination of 6-O-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea therapy should be achieved by depleting 6-O-methylguanine DNA methyltransferase in the target tumor for 24 h with minimal depletion in normal tissues
medicine
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clonal selection of AGT mutants during trteatment with O6-benzylguanine plus an alkylator may produce resistance to this intervention in clinical settings
medicine
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DNA hypermethylation and silencing of MGMT are frequent and rather early events in esophageal squamous cell carcinogenesis. Hypermethylation and inactivation of MGMT may be prevented or reversed by dietary polyphenols, (-)-epigallocatechin-3-gallate and genistein, for the prevention of carcinogenesis
medicine
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O4-benzylfolic acid is 30times more active than O6-benzylguanine against the wild-type alkyltransferase, inactivation of P140K mutant alkyltransferase. Inhibitor shows promise as an agent for possible tumor-selective alkyltransferase inactivation superior toO6-benzylguanine as a chemotherapy adjuvant
medicine
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AGT-DNA cross-linking is a likely mechanism of 1,2,3,4-diepoxybutane-mediated cytotoxicity in cells expressing this important repair protein
medicine
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alkyltransferase activity in tumors protects them from therapeutic agents such as temozolomide and N,N'-bis(2-chloroethyl)-N-nitrosourea, polymorphisms in the AGT gene
medicine
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cigarette smoking not only induces O6-alkylguanine lesions, it inhibits the repair of these adducts by MGMT, O6-alkylguanine adducts are well established carcinogenic lesions and decreased repair of such lesions may increase susceptibility to lung cancer in smokers
medicine
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combining cisplatin and temozolomide is based on the potential for improved antitumour activity, combination is well tolerated in children and adolescents, generating no toxicity greater than that of the single agents
medicine
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even slight alterations in the active site pocket of AGT do not prevent its ability to protect cells from alkylating agents, can block the paradoxical enhancement of the genotoxicity of the larger alpha,omega-dihaloalkanes by reducing the reaction with Cys145
medicine
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expression of additional AGT in a variety of tissues in transgenic mice protects against carcinogenesis
medicine
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highly significant correlation between AGT protein expression assessed by immunohistochemistry and AGT activity assessed by HPLC, marginal statistically significant correlation between immunohistochemistry and real-time methylation-specific PCR, and no significant correlation between AGT protein activity assessed by HPLC versus real-time methylation-specific PCR. Cross-tabulation of immunohistochemistry and real-time methylation-specific PCR data based on prognostic groups shows no significant relationship, suggesting that one assay cannot be used interchangeably for another, thus the results cannot be used to guide glioma therapy decisions
medicine
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inhibition of tumor suppressor p53 by RNAi is accompanied by down-regulation of MGMT gene expression, but is not associated with a discernible change in the pattern of MGMT promoter methylation
medicine
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MGMT can modulate cytotoxicity of camptothecin-derived topoisomerase I inhibitors, MGMT overexpression reveals more resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea, camptothecin, 7-ethyl-10-hydrocamptothecin and topotecan, alteration of MGMT expression coincides with camptothecin-induced cell death and poly(ADP-ribose) polymerase cleavage
medicine
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MGMT significantly protects against in vivo temozolomide-induced mutations
medicine
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temozolomide appears to be a good candidate for use in conjunction with hyperthermia for regional chemotherapy of melanoma
medicine
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transgenic rats expressing Ada-C are resistant to mammary tumor induction by N-methyl-N-nitrosourea but not by N-ethyl-N-nitrosourea
medicine
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tumor suppressor p53 positively regulates MGMT gene expression in murine astrocytes
medicine
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inhibition of tumour MGMT by pseudosubstrates to overcome tumour resistance is under clinical evaluation, MGMT overexpression in haematopoietic stems cells has been shown to protect normal cells against the myelosuppressive effects of chemotherapy
medicine
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MGMT can confer resistance to the cancer chemotherapeutic effects of the class of DNA damaging drugs, inactivation of MGMT is thus a practical approach to improving the efficacy of such agents
medicine
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the results suggest that expression of MGMT could enhance the capacity of bone marrow-derived cells to repopulate lung epithelium, and when used in combination with a gene of interest, MGMT could have therapeutic applications
medicine
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determination of MGMT in peripheral blood mononuclear cells can identify patients at greatest risk of toxicity with O6-alkylating agent chemotherapy or who are suitable for dose intensification, MGMT protects against the toxic effects of O6-alkylating agents
medicine
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MGMT is a factor of chemoresistance to alkylating drugs in anaplastic ependymomas
medicine
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the combination of high thymidylate synthase and low O6-methylguanine-DNA methyltransferase expression is a significant predictor of a poor response to fluoropyrimidine treatment
medicine
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the enzyme protein expression is an unfavorable prognostic factor for patients with gliosarcoma
medicine
a deficient enzyme status in pancreatic neuroendocrine tumors is not associated with a better response to temozolomide-based chemotherapy and cannot be used as a predictive marker to lead treatment decisions
medicine
a larger number of methylated CpG sites in the enzyme promoter region is associated with a favorable outcome of medulloblastoma
medicine
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the enzyme methylation status is associated with longer survival in female patients compared with unmethylated females