Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.37 (DNA methyltransferase)
4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have demonstrated that optimal reversal of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance requires complete inactivation of the DNA repair protein O(6)-methylguanine DNA methyltransferase (MGMT) for at least 24 h following BCNU administration. In preparation for clinical trials at this institution, this study was undertaken to compare the efficacy of a conventional single-bolus dose versus double-bolus dose treatments with O(6)-benzylguanine (BG) in depleting MGMT activity in vivo. In xenograft human glioma SF767 tumors, a single 30-mg/kg bolus dose of BG completely inhibited MGMT activity for at least 8 h, but approximately 50% of the basal MGMT activity recovered within 24 h. To sustain the MGMT depletion for 24 h, a second bolus injection of BG at escalating doses was administered 8 h after the first dose. Second bolus doses of 5, 10, and 15 mg/kg BG attenuated the MGMT recovery in a dose-dependent manner compared with the single 30-mg/kg BG dose alone. When the 15-mg/kg BG dose was administered 8 h after the 30-mg/kg initial dose, MGMT activity was completely inactivated in the tumor xenografts for 24 h. This double-bolus BG treatment also depleted MGMT activity in normal murine tissues, including the liver, kidney, lung, brain, spleen, and bone marrow; and the kinetics of MGMT recovery varied among these tissues. When combined with BCNU treatment, the double-bolus BG treatment would be expected to produce greater antitumor activity in future trials than the conventional single-bolus BG treatment.
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PMID:Comparison of single- versus double-bolus treatments of O(6)-benzylguanine for depletion of O(6)-methylguanine DNA methyltransferase (MGMT) activity in vivo: development of a novel fluorometric oligonucleotide assay for measurement of MGMT activity. 1130 39

Alkylating agents, which are metabolized by glutathione S-transferase (GST), have an important role in the etiology of cancer by forming mutagenic DNA adducts. Previous studies have shown that DNA repair protein, O6-methylguanine DNA methyltransferase, repairs these mutagenic DNA adducts and its activity is correlated with the resistance of human tumors to alkylating agent-based anti-cancer drugs. However, little is known about GST and O6-methylguanine DNA methyltransferase activities in patients with thyroid cancer in vivo. We measured the activities of GST and O6-methylguanine DNA methyltransferase in the leukocytes from patients with papillary thyroid carcinoma and healthy controls. The GST activity was significantly higher in men than in women, and it was negative correlated with age in men whereas it was unchanged in women in the control group. Both GST and O6-methylguanine DNA methyltransferase activities were significantly increased in the patient group. There were no age and sex-related changes in the O6-methylguanine DNA methyltransferase activity in both the control and patient groups. These results suggest that leukocyte GST and O6-methylguanine DNA methyltransferase activities were increased with thyroid cancer. This may be related to the resistance to chemotherapy exhibited by patients with thyroid cancer.
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PMID:Glutathione S-transferase and O6-methylguanine DNA methyl transferase activities in patients with thyroid papillary carcinoma. 1244 29

Strategies that confer chemoresistance to hematopoietic stem and progenitor cells have two important future applications in the treatment of cancer and genetic diseases. Because dose-intensification of many cancer chemotherapy protocols is limited by severe hematopoietic toxicities, generation of primitive hematopoietic cells resistant to DNA damage mediated by chemotherapy may protect patients from life-threatening blood cytopenias. In addition, in the context of genetic diseases, overexpression of a chemoresistance gene in stem and progenitor cells may allow for the enrichment of small numbers of transduced cells that would not possess an in vivo selective advantage. In this report, I discuss studies that use the DNA repair protein O6-methylguanine DNA methyltransferase to protect hematopoietic cells from alkylator therapy. I focus on investigations evaluating the ability of O6-methylguanine-DNA methyltransferase mutant proteins to confer heightened resistance to alkylator-mediated DNA damage in vivo.
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PMID:In vivo protection of hematopoietic cells from alkylator-mediated DNA damage. 1290 32

The major mechanism of tumor cell resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is the DNA repair protein O(6)-methylguanine DNA methyltransferase (MGMT). This repair system can be temporarily inhibited by the free base O(6)-benzylguanine (BG), which depletes cellular MGMT activity and sensitizes tumor cells and xenografts to BCNU. In clinical studies, the combination of BG and BCNU enhanced the myeloid toxicity of BCNU, thereby reducing the maximum tolerated dose. We have shown previously that retroviral expression of the P140K mutant of MGMT (MGMT-P140K) in murine and human hematopoietic cells produces significant resistance of bone marrow cells to low-dose, combination BG and BCNU treatment in vivo. In the current study, we investigated the ability of bone marrow transplantation with MGMT-P140K-transduced hematopoietic cells to protect against an intensive antitumor treatment regimen of combination BG and BCNU in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The donor marrow cells underwent in vivo BG and BCNU selection before transplantation, allowing infusion of a highly selected population of transduced cells. Tolerance to the intensive BG and BCNU treatment was markedly improved in secondary MGMT-P140K-transplanted mice (n = 19) compared to untransplanted mice (n = 15), as indicated by blood counts and survival rate. The dose-intensified BG and BCNU therapy produced significant growth delays of glioma xenografts in MGMT-P140K-transplanted mice, extending the tumor doubling time by >40 days. These results demonstrate that MGMT-P140K-transduced bone marrow protects against BG and BCNU combination therapy in vivo and allows dose-intensified treatment of tumor xenografts.
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PMID:Hematopoietic expression of O(6)-methylguanine DNA methyltransferase-P140K allows intensive treatment of human glioma xenografts with combination O(6)-benzylguanine and 1,3-bis-(2-chloroethyl)-1-nitrosourea. 1470 73

Methylating agents are involved in bladder carcinogenesis. O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes methyl group from O6-methylguanine and thus plays an important role in the etiology of cancer. We hypothesized that two MGMT polymorphisms in exon 3, C16195T (or MGMT L53L) and C16286T (or MGMT L84F) are associated with risk of bladder cancer. In a hospital-based case-control study of 167 patients with bladder cancer and 204 cancer-free controls frequency-matched by age, sex, smoking status, and alcohol use, we genotyped these two MGMT polymorphisms. We found that these two polymorphisms alone had a non-significant main effect on risk of bladder cancer. However, when these two polymorphisms were evaluated together, individuals with the combined genotypes or haplotypes with one or more variant alleles (i.e. the 16195T and 16286T alleles) had statistically significantly increased risk of bladder cancer (adjusted odd ratio [OR]=1.67, 95% confidence interval [CI], 1.01-2.77) compared with those with no variant allele. In the stratification analysis, the risk of bladder cancer was increased in a dose-response manner as the age increased (P(trend)=0.010), and the increased risk was more pronounced among old subjects (>65 years) (adjusted OR=2.51, 95% CI, 1.05-6.04), men (1.76, 1.00-3.10), and non-drinkers (1.91, 1.08-3.36). In conclusion, these two MGMT polymorphisms may jointly play a role, in the etiology of bladder cancer in southern Chinese population. Larger studies are warranted to validate our findings.
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PMID:Exon 3 polymorphisms and haplotypes of O6-methylguanine-DNA methyltransferase and risk of bladder cancer in southern China: a case-control analysis. 1588 89

The human DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) dealkylates mutagenic O6-alkylguanine lesions within DNA in an irreversible reaction which results in inactivation of the protein. MGMT also provides resistance of tumours to alkylating agents used in cancer chemotherapy and its inactivation is therefore of particular clinical importance. We describe a post-DNA synthesis strategy which exploits the novel, modified base 2-amino-6-methylsulfonylpurine and allows access for the first time to a wide variety of oligodeoxyribonucleotides (ODNs) containing O6-alkylguanines. One such ODN containing O6-(4-bromothenyl)guanine is the most potent inactivator described to date with an IC50 of 0.1 nM.
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PMID:Novel synthesis of O6-alkylguanine containing oligodeoxyribonucleotides as substrates for the human DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT). 1660 28

O(6)-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that restores mutagenic O(6)-methylguanine to guanine. MGMT methylation is frequently observed in sporadic colorectal cancer and was recently correlated with the C>T allele at SNP rs16906252, within the transcriptional enhancer element of the promoter. MGMT methylation has also been associated with KRAS mutations, particularly G>A transitions. We studied 1123 colorectal carcinoma to define the molecular and clinicopathological profiles associated with MGMT methylation. Furthermore, we assessed factors contributing to MGMT methylation in the development of colorectal cancer by studying the allelic pattern of MGMT methylation using SNP rs16906252, and the methylation status of neighbouring genes within 10q26 in selected tumours and matched normal colonic mucosa. MGMT methylation was detected by combined bisulphite restriction analysis in 28% of tumours and was associated with a number of characteristics, including CDKN2A methylation, absent lymphovascular space invasion and KRAS mutations (but not specifically with KRAS G>A transitions). In a multivariate analysis adjusted for age and sex, MGMT methylation was associated with the T allele of SNP rs16906252 (P<0.0001, OR 5.5, 95% CI 3.8-7.9). Low-level methylation was detected by quantitative methylation-specific PCR in the normal colonic mucosa of cases, particularly those with a correspondingly methylated tumour, as well as controls without neoplasia, and this was also associated with the C>T SNP. We show that the T allele at SNP rs16906252 is a key determinant in the onset of MGMT methylation in colorectal cancer, whereas the association of methylation at MGMT and CDKN2A suggests that these loci may be targets of a common mechanism of epigenetic dysregulation.
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PMID:MGMT methylation is associated primarily with the germline C>T SNP (rs16906252) in colorectal cancer and normal colonic mucosa. 1973 44

Azoxymethane (AOM) is an alkylating agent that generates mutagenic and carcinogenic O(6)-methylguanine (O(6)meG) adducts in DNA. O(6)meG has been detected in human colonic DNA; hence, understanding the innate cellular events occurring in response to the formation of O(6)meG is important in developing preventive strategies for colorectal cancer. We explored the time-course, dose-response, and kinetics of O(6)meG formation and its removal by the DNA repair protein, O(6)-methylguanine DNA methyltransferase (MGMT), and apoptosis. In rats given AOM (10 mg/kg), the formation of O(6)meG occurs within 2 h of exposure, accompanied by rapid depletion of MGMT activity and followed by the induction of an acute apoptotic response that peaks at 6-8 h. MGMT repair and apoptosis are dependent on AOM dose and O(6)meG load. Apoptosis is initiated only when a high O(6)meG load is present and MGMT activity is fully depleted. AOM, 10 mg/kg, overwhelms MGMT repair for about 96 h and renewed MGMT activity is only observed once O(6)meG is no longer detectable. A threshold for apoptosis is observed at 6 h after 6 mg/kg AOM, when a high O(6)meG persists and MGMT activity is very low. These data suggest that apoptosis is probably triggered by O(6)meG, but only once the capacity of MGMT to repair O(6)meG is exhausted. In the colonic epithelium, apoptosis may be complementary to MGMT, in terms of minimising potentially mutagenic events and maintaining a healthy genome.
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PMID:Repair and removal of azoxymethane-induced O6-methylguanine in rat colon by O6-methylguanine DNA methyltransferase and apoptosis. 2414 Mar 86

Ganglioglioma (GG) is an uncommon brain parenchymal neoplasm. Although most cases have indolent clinical behaviour, a subgroup of GGs does recur, especially in patients with unresectable disease. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from O6-guanine in DNA. Lack of MGMT protein expression immunohistochemically is related to drug responses in patients with malignant glioma treated with alkylating agents. Furthermore, MGMT promoter methylation has also been investigated as an independent favourable prognostic factor for glioblastoma. The primary management is surgical resection for GGs and gross total resection is recommended. Despite infrequent use of chemotherapy for low-grade GGs, it was still introduced to a subset of patients, especially those who had unresectable disease. We assessed clinicopathological features of nine cases of low-grade GG to further elucidate the relationship between the status of the MGMT protein expression and the prognosis. This series included four men and five women with a mean age of 21.6 years at the first surgery. The mean postoperative follow-up period was 6 years. Only two patients had recurrent disease after 1.7 and 3.2 years of the first surgery. Immunohistochemically, 11.1% exhibited 3+ nuclear staining for MGMT protein, 11.1% exhibited 2+ staining, 33.3% exhibited 1+ staining, and 44.4% exhibited 0 staining. Tumours with more intensive MGMT protein expression (2+~3+ immunostaining) tended to recur more frequently (p < 0.05), corresponding to the worse prognostic predictive value of intensive MGMT staining.
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PMID:The prognostic impact of MGMT expression on low-grade gangliogliomas: a clinicopathological and immunohistochemical study. 2437 55

Glioblastoma is the most common and aggressive primary brain tumor in adults. Defining histopathologic features are necrosis and endothelial proliferation, resulting in the assignment of grade IV, the highest grade in the World Health Organization (WHO) classification of brain tumors. The classic clinical term "secondary glioblastoma" refers to a minority of glioblastomas that evolve from previously diagnosed WHO grade II or grade III gliomas. Specific point mutations of the genes encoding isocitrate dehydrogenase (IDH) 1 or 2 appear to define molecularly these tumors that are associated with younger age and more favorable outcome; the vast majority of glioblastomas are IDH wild-type. Typical molecular changes in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signaling. Standard treatment of glioblastoma includes surgery, radiotherapy, and alkylating chemotherapy. Promoter methylation of the gene encoding the DNA repair protein, O(6)-methylguanyl DNA methyltransferase (MGMT), predicts benefit from alkylating chemotherapy with temozolomide and guides choice of first-line treatment in elderly patients. Current developments focus on targeting the molecular characteristics that drive the malignant phenotype, including altered signal transduction and angiogenesis, and more recently, various approaches of immunotherapy.
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PMID:Glioblastoma. 2694 67


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