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Thomas Efferth - One of the best experts on this subject based on the ideXlab platform.
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Protein expression profiles indicative for drug resistance of non-small cell lung cancer
British Journal of Cancer, 2002Co-Authors: Manfred Volm, R Koomägi, Jürgen Mattern, Thomas EfferthAbstract:Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro . The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-π, metallothionein, O^6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-π, O^6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-π, O^6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein).
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Protein expression profiles indicative for drug resistance of non-small cell lung cancer
British Journal of Cancer, 2002Co-Authors: Manfred Volm, R Koomägi, Jürgen Mattern, Thomas EfferthAbstract:Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro . The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-π, metallothionein, O^6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-π, O^6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-π, O^6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein).
James G. Herman - One of the best experts on this subject based on the ideXlab platform.
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Generating mutations but providing chemosensitivity: the role of O^6-methylguanine DNA methyltransferase in human cancer
Oncogene, 2004Co-Authors: Manel Esteller, James G. HermanAbstract:O^6-methylguanine DNA methyltransferase (MGMT) is a key enzyme in the DNA repair network. MGMT removes mutagenic and cytotoxic adducts from O^6-guanine in DNA, the preferred point of attack of many carcinogens (i.e. methylnitrosourea) and alkylating chemotherapeutic agents (i.e. BCNU, temozolamide, etc.). Hypermethylation of the CpG island located in the promoter region of MGMT is primarily responsible for the loss of MGMT function in many tumor types. The methylation-mediated silencing of MGMT has two consequences for cancer. First, tumors with MGMT methylation have a new mutator phenotype characterized by the generation of transition point mutations in genes involved in cancer etiology, such as the tumor suppressor p53 and the oncogene K-ras. Second, MGMT hypermethylation demonstrates the possibility of pharmacoepigenomics: methylated tumors are more sensitive to the killing effects of alkylating drugs used in chemotherapy. These recent results underscore the importance of MGMT in basic and translational cancer research.
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inactivation of the dna repair gene mgmt and the clinical response of gliomas to alkylating agents
The New England Journal of Medicine, 2000Co-Authors: Manel Esteller, J Garciafoncillas, Esther Andion, Oscar F Hidalgo, Vicente Vanaclocha, Steven N Goodman, Stephen B. Baylin, James G. HermanAbstract:Background The DNA-repair enzyme O 6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of t...
Bernd Kaina - One of the best experts on this subject based on the ideXlab platform.
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Lipoic acid inhibits the DNA repair protein O 6-methylguanine-DNA methyltransferase (MGMT) and triggers its depletion in colorectal cancer cells with concomitant autophagy induction.
Carcinogenesis, 2015Co-Authors: Anja Göder, Alexander Kraus, Bastian Dörsam, Nina Seiwert, Bernd Kaina, Georg Nagel, Jörg FahrerAbstract:Alkylating agents are present in food and tobacco smoke, but are also used in cancer chemotherapy, inducing the DNA lesion O (6)-methylguanine. This critical adduct is repaired by O (6)-methylguanine-DNA methyltransferase (MGMT), resulting in MGMT inactivation and degradation. In the present study, we analyzed the effects of the natural disulfide compound lipoic acid (LA) on MGMT in vitro and in colorectal cancer cells. We show that LA, but not its reduced form dihydrolipoic acid, potently inhibits the activity of recombinant MGMT by interfering with its catalytic Cys-145 residue, which was partially reversible by N-acetyl cysteine. Incubation of HCT116 colorectal cancer cells with LA altered their glutathione pool and caused a decline in MGMT activity. This was mirrored by LA-induced depletion of MGMT protein, which was not attributable to changes in MGMT messenger RNA levels. Loss of MGMT protein coincided with LA-induced autophagy, a process resulting in lysosomal degradation of proteins, including presumably MGMT. LA-stimulated autophagy in a p53-independent manner as revealed by the response of isogenic HCT116 cell lines. Knockdown of the crucial autophagy component beclin-1 and chemical inhibitors blocked LA-induced autophagy, but did not abrogate LA-triggered MGMT degradation. Concomitant with MGMT depletion, LA pretreatment resulted in enhanced O (6)-methylguanine levels in DNA. It also increased the cytotoxicity of the alkylating anticancer drug temozolomide in temozolomide-resistant colorectal cancer cells. Taken together, our study showed that the natural compound LA inhibits MGMT and induces autophagy. Furthermore, LA enhanced the cytotoxic effects of temozolomide, which makes it a candidate for a supplement in cancer therapy.
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O(6)-methylguanine-DNA methyltransferase (MGMT): impact on cancer risk in response to tobacco smoke.
Mutation research, 2011Co-Authors: Markus Christmann, Bernd KainaAbstract:Tobacco, smoked, snuffed and chewed, contains powerful mutagens and carcinogens. At least three of them, N-dimethylnitrosamine, N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, attack DNA at the O(6)-position of guanine. The resulting O(6)-alkylguanine adducts are repaired by the suicide enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is known to protect against the mutagenic, genotoxic and carcinogenic effects of monofunctional alkylating agents. While in rat liver MGMT was shown to be subject to regulation by genotoxic stress leading to adaptive changes in its activity, in humans evidence of adaptive modulation of MGMT levels is still lacking. Several polymorphisms are known, which are suspected to impact on the risk of developing cancer. In this review we focus on three questions: (a) Has tobacco consumption by smoking or chewing an impact on MGMT expression and MGMT promoter methylation in normal and tumor tissue? (b) Is there an association between MGMT polymorphisms and cancer risk and is this risk related to smoking? (c) Does MGMT protect against tobacco-associated cancer? There are several lines of evidence for an increase of MGMT activity in the normal tissue of smokers compared to non-smokers. Furthermore, in tumors developed in smokers a tendency towards an increase of MGMT expression was found. The data points to the possibility that agents in tobacco smoke are able to trigger upregulation of MGMT in normal and tumor tissue. For MGMT promoter methylation data is conflicting. There is some evidence for an association between MGMT polymorphisms and smoking-induced cancer risk. The key question whether or not MGMT protects against tobacco smoke-induced cancer is difficult to answer since prospective studies on smokers versus non-smokers are lacking and appropriate animal studies with MGMT transgenic mice exposed to the complex mixture of tobacco smoke have not been performed, which indicates the need for further explorations.
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Targeting O ^6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy
Cellular and Molecular Life Sciences, 2010Co-Authors: Bernd Kaina, Geoffrey P Margison, Markus ChristmannAbstract:O ^6-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O ^6-methylguanine and O ^6-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O ^6-benzylguanine and O ^6-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.
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Synthesis of 2-amino-6-(2-[18F]fluoro-pyridine-4-ylmethoxy)-9-(octyl-β-d-glucosyl)-purine: a novel radioligand for positron emission tomography studies of the O6-methylguanine-DNA methyltransferase (MGMT) status of tumour tissue
Tetrahedron Letters, 2002Co-Authors: Ralf Schirrmacher, Ute Mühlhausen, Benkt. Wangler, Jost Reinhard, Gerd Nagel, Esther Schirrmacher, Markus Piel, Bernd Kaina, Manfred Wiessler, Frank RoschAbstract:Abstract The synthesis of the novel glucose conjugated O 6 -methylguanine-DNA methyltransferase (MGMT) inhibitor 2-amino-6-(2-[ 18 F]fluoro-pyridine-4-ylmethoxy)-9-(octyl-α- d -glucosyl)-purine is reported. This compound might serve as a radiotracer for the determination of the MGMT status of tumour tissue.
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p53 is involved in regulation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) by DNA damaging agents
Oncogene, 1998Co-Authors: Thomas Grombacher, Uta Eichhorn, Bernd KainaAbstract:p53 is involved in regulation of the DNA repair gene O 6 -methylguanine-DNA methyltransferase (MGMT) by DNA damaging agents
Manfred Volm - One of the best experts on this subject based on the ideXlab platform.
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Protein expression profiles indicative for drug resistance of non-small cell lung cancer
British Journal of Cancer, 2002Co-Authors: Manfred Volm, R Koomägi, Jürgen Mattern, Thomas EfferthAbstract:Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro . The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-π, metallothionein, O^6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-π, O^6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-π, O^6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein).
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Protein expression profiles indicative for drug resistance of non-small cell lung cancer
British Journal of Cancer, 2002Co-Authors: Manfred Volm, R Koomägi, Jürgen Mattern, Thomas EfferthAbstract:Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro . The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-π, metallothionein, O^6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-π, O^6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-π, O^6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein).
Stanton L Gerson - One of the best experts on this subject based on the ideXlab platform.
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rapid repair of o6 methylguanine dna adducts protects transgenic mice from n methylnitrosourea induced thymic lymphomas
Cancer Research, 1994Co-Authors: Lili Liu, Esther Allay, Luba Dumenco, Stanton L GersonAbstract:The methylating agent N -methylnitrosourea (MNU) is biased, surprisingly, in its carcinogenic potential toward the mouse thymus. Previous studies have shown that single doses of MNU administered to adult mice induced thymic lymphomas in over 80% of mice, while transgenic mice expressing high levels of the human O 6-alkylguanine-DNA alkyltransferase gene in the thymus ( MGMT-CD2 transgenics) were protected from developing MNU-induced lymphomas. The mechanism of this protection was examined in this report. In nontransgenic mice given a lymphomagenic dose of 80 mg/kg MNU, depletion of thymic alkyltransferase activity occurred within 3 h and remained undetectable for the subsequent 192 h; whereas in MGMT-CD2 -transgenic mice, this dose of MNU did not deplete thymic alkyltransferase, and the lowest level of alkyltransferase was still 10-fold higher than the constitutive level of thymic alkyltransferase in nontransgenic mice. Likewise, the level of O 6-methylguanine adducts detected in the thymus of nontransgenic mice was 96 pg/µg guanine 3 h after MNU compared to only 8 pg/µg guanine in transgenic mice. By 18 h, the level of O 6-methylguanine in MGMT-CD2 -transgenic mice was below 2 pg/µg guanine, compared to over 70 pg/µg guanine in nontransgenic mice. In contrast, no differences were noted in the liver between groups because the MGMT transgene is not expressed in the liver of this strain of mouse. Our data establish that rapid O 6-methylguanine-DNA adduct repair due to enhanced levels of alkyltransferase in MGMT-CD2 -transgenic mice blocks the initiation of MNU-induced carcinogenesis.
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Lack of correlation between DNA methylation and hepatocarcinogenesis in rats and hamsters treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
Carcinogenesis, 1992Co-Authors: Andre Castonguay, Stanton L GersonAbstract:Previous studies have demonstrated that the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced liver tumors in F344 rats but not in Syrian golden hamsters. The aim of this study was to determine whether there was a correlation between the persistence of O 6 -methylguanine (O 6 -mGua) adducts and the rate of recovery of O 6 -methylguanine-DNA methyltransferase (O 6 -mGuaT) after depletion in the liver and susceptibility to NNK in F344 rat and Syrian golden hamster injected s.c. with NNK (80 mg/kg)
