MGMT: its role in cancer aetiology and cancer therapeutics

Gerson, Stanton L.

doi:10.1038/nrc1319

Cited by 737 publications

(593 citation statements)

References 94 publications

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“…36 It plays the role of removing alkylating adducts induced by temozolomide treatment, thereby counteracting its antineoplastic action. 37,38 It appears that high tumor expression of MGMT confers resistance to temozolomide. It is widely believed that low-level expression in a wide spectrum of human tumors results from epigenetic silencing of the MGMT gene, largely because of hypermethylation of its promoter.…”

Section: Temozolomidementioning

confidence: 99%

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Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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Section: Temozolomidementioning

confidence: 99%

“…During tumorigenesis, loss of MGMT expression and impaired capability of DNA repair have been observed. 37,38,41 In contrast, MGMT overexpression has prevented carcinogenesis in mouse models. 37 In low-grade astrocytomas, lack of MGMT expression has been considered a marker of malignant transformation.…”

Section: Mgmt Immunoexpressionmentioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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“…9 MGMT is a key player in the defence against the cytotoxic, mutagenic and carcinogenic effects of O 6 MeG that has been studied in cell, cancer and animal models. 10 When O 6 MeG is not repaired by MGMT, it will mispair with thymine during DNA replication 11 and, therefore, in the absence of mismatch repair (MMR), and a second round of replication, indues GC to AT point mutations. 12 In MMR competent cells, the O 6 MeG/thymine mismatch is bound by MutSa, 13 a heterodimer comprised of the proteins MSH2 and MSH6.…”

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confidence: 99%

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

Roos¹,

Christmann²,

Fraser

et al. 2007

Cell Death Differ

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Exposure of stem cells to genotoxins may lead to embryonic lethality or teratogenic effects. This can be prevented by efficient DNA repair or by eliminating genetically damaged cells. Using undifferentiated mouse embryonic stem (ES) cells as a pluripotent model system, we compared ES cells with differentiated cells, with regard to apoptosis induction by alkylating agents forming the highly mutagenic and killing DNA adduct O 6 -methylguanine. Upon treatment with N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG), ES cells undergo apoptosis at much higher frequency than differentiated cells, although they express a high level of the repair protein O 6 -methylguanine-DNA methyltransferase (MGMT). Apoptosis induced by MNNG is due to O 6 -methylguanine DNA adducts, since inhibition of MGMT sensitized ES cells. The high sensitivity of ES cells to O 6 -methylating agents is due to high expression of the mismatch repair proteins MSH2 and MSH6 (MutSa), which declines during differentiation. High MutSa expression in ES cells was related to a high hyperphosphorylated retinoblastoma (ppRb) level and E2F1 activity that upregulates MSH2, causing, in turn, stabilization of MSH6. Non-repaired O 6 -methylguanine adducts were shown to cause DNA doublestranded breaks, stabilization of p53 and upregulation of Fas/CD95/Apo-1 at significantly higher level in ES cells than in fibroblasts. The high apoptotic response of ES cells to O 6 -methylguanine adducts may contribute to reduction of the mutational load in the progenitor population.

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“…19 O6 methylguanine DNA methyl-transferase (MGMT, 10q26) encodes a DNA repair protein that removes mutagenics and cytotoxic adducts at O 6 of guanine and, therefore plays an important role in maintaining normal cell physiology and genomic stability. 20 Methylated regions of the MGMT promoter are in a 'closed' nucleosome structure, that is associated with alterations in heterochromatin and with promoter methylation of other cancer-associated genes. MGMT promoter methylation is only found in tumours.…”

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confidence: 99%

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

et al. 2006

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Monoclonal gammopathies are a group of disorders characterized by clonal proliferation and accumulation of immunoglobulin-producing plasma cells. Multiple myeloma and monoclonal gammopathy of undetermined significance are the most common monoclonal gammopathies; the two comprise a spectrum of disorders, ranging from a relatively benign disease, monoclonal gammopathy of undetermined significance, to a malignant disease, multiple myeloma. Aberrant promoter methylation represents a primary mechanism of gene silencing during tumorigenesis. DNA repair systems act to maintain genome integrity in the presence of replication errors, environmental insults, and the cumulative effects of aging. The methylation patterns of two genes implicated in DNA repair, O6 methylguanine DNA methyl-transferase (MGMT) and human mutL homologue1 (hMLH1) have been detected in various solid tumours. With the purpose of studying the gene silencing of MGMT and hMLH1 in plasma cell disorders, we investigated the methylation status and expression of both genes in: 29 cases of multiple myeloma; one case of plasma cell leukaemia; 13 cases of monoclonal gammopathy of undetermined significance; and two cases of polyclonal plasmacytosis, using methylationspecific polymerase-chain reaction and immunohistochemical techniques. Methylation frequencies for MGMT were 23% in multiple myeloma and 8% in monoclonal gammopathy of undetermined significance. It was 10% for hMLH1 in multiple myeloma. None of the patients diagnosed with monoclonal gammopathy of undetermined significance had hMLH1 hypermethylated. In addition, 50% of myeloma cases had a loss of hMLH1 expression, whereas silencing of MGMT was observed in 43% of myeloma and 36% of samples with monoclonal gammopathy of undetermined significance. This study indicates that repair pathway defects play a role in the pathogenesis and evolution of monoclonal gammopathies, and suggests that inactivation of hMLH1 could be implicated in multiple myeloma tumorigenesis.

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MGMT: its role in cancer aetiology and cancer therapeutics

Cited by 737 publications

References 94 publications

Treatment of pituitary neoplasms with temozolomide

Treatment of pituitary neoplasms with temozolomide

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

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