O<sup>6</sup>-Methylguanine-DNA Methyltransferase in Human Normal and Malignant Lung Tissues

Citron, Marc L.; Schoenhaus, Michelle; Graver, Michael; Hoffman, Mark A.; Lewis, Mark P.; Wasserman, Patricia; Niederland, Marta; Kahn, Leonard B.; White, Agnes; Yarosh, Daniel B.

doi:10.3109/07357909309024850

Cited by 47 publications

(44 citation statements)

References 6 publications

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“…22 MGMT promoter hypermethylation and absence of MGMT activity were reported in several human tumors including colon and lung cancers, glioma, lymphoma and gastric carcinoma. 2,6,8,[23][24][25][26] In our study, MGMT hypermethylation was present in 32 of 83 (39%) HCC cases, but it was not found in 2 HCC cell lines. This frequency is lower than that observed in secondary glioblastoma (75%), 27 but similar to that in colon cancer (38%) 2 and gastric carcinoma (31%).…”

Section: Discussionmentioning

confidence: 95%

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Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma

Zhang

Chen

Ahsan

et al. 2002

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is one of the most common human malignant neoplasms with almost 500,000 estimated new cases enumerated worldwide during the most recent year surveyed. 1 Its etiology is not completely clear, but strong associations exist with hepatitis B and C virus infection and several dietary or environmental factors, including aflatoxin B 1 (AFB 1 ). The molecular pathogenesis of HCC appears to involve multiple genetic aberrations in the molecular control of hepatocyte proliferation, differentiation and death and the maintenance of genomic integrity. This process is influenced by the cumulative activation and inactivation of oncogenes, tumor suppressor genes and other genes. 0 6 -methylguanine-DNA methyltransferase (MGMT) is a 22,000 kd protein that is critical for the rapid reversal of methylation of guanine. 2,3 Alkylation of DNA at the O 6 position of guanine is a potentially mutagenic lesion mainly due to the tendency of O 6 -methylguanine to pair with thymine during replication, resulting in the conversion of a guanine-cytosine to an adenine-thymine base pair. 4 The level of MGMT activity varies greatly between species and cell types. 5,6 In humans, liver contains the highest level of MGMT activity. 5 The amounts of MGMT protein are decreased in some tumors and tumor cell lines. 7,8 Loss of expression is rarely due to deletion, mutation or rearrangement of the MGMT gene, but methylation of a discrete region of the CpG island of MGMT has been associated with the silencing of the gene in cell lines. 9 -11 Hypermethylation of normally unmethylated CpG islands in the promoter regions of many genes correlates with loss of transcription. 12 Early MGMT inactivation has been linked with gene mutation in some critical growth regulatory genes; K-ras mutations, especially G to A, are more common in colon cancer after MGMT inactivation. 13 Inactivation of the MGMT gene by promoter hypermethylation has been found in brain tumors, colon cancer, lung cancer and other cancers. 2 Recently, it was reported that MGMT promoter hypermethylation was present significantly more often in tumors with a G to A mutation in p53 than in tumors with other types of p53 mutation or in tumors with wild-type p53. 14,15 In our study, we explored the possible role of inactivation of MGMT in the development of HCC. We had previously analyzed these samples for p53 gene and protein alterations as well as measured DNA damage levels caused by the dietary carcinogen AFB 1 . 16 More recently, we reported a high frequency of promoter hypermethylation of the human ras association domain family 1A (RASSF1A) gene in HCC. 17 Thus, we also investigated the relationship between these biomarkers and methylation status.

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Section: Discussionmentioning

confidence: 95%

“…4 The level of MGMT activity varies greatly between species and cell types. 5,6 In humans, liver contains the highest level of MGMT activity. 5 The amounts of MGMT protein are decreased in some tumors and tumor cell lines.…”

mentioning

confidence: 99%

Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma

Zhang

Chen

Ahsan

et al. 2002

Intl Journal of Cancer

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“…This is in accordance with previous work of this and other groups reporting up to 24% of gliomas lacking detectable MGMT (previously defined as Mer 2 ). 26,[32][33][34] Interestingly, the frequency of MGMT lacking GBMs does not correspond with the frequency of MGMT promoter methylation, for which 45% of untreated GBM harbor epigenetic silencing of the MGMT gene. 19 Nevertheless, the frequency of 17.5% is clearly higher than in other groups of solid tumors for which maximally 5% were reported to be MGMT deficient.…”

Section: Expression and Regulation Of Mgmtmentioning

confidence: 99%

MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome

Wiewrodt

Nagel²,

Dreimüller

et al. 2007

Intl Journal of Cancer

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The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) plays a pivotal role in alkylating drug resistance. Here, we determined MGMT activity in primary and recurrent glioblastomas (GBM, WHO grade IV) of patients who received radiation therapy (RT) or RT plus chemotherapy with alkylating agents (temozolomide, chloroethylnitrosoureas). The mean MGMT activity of untreated GBM was 37 6 45 (range 0-205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 6 50 (13-194) to 68 6 44 (14-143) and 182 6 163 (64-423) fmol/mg protein, respectively. Comparing patients who received RT only with RT plus chemotherapy, a significant increase of MGMT in 1st recurrences was only found after treatment with RT plus chemotherapy, indicating either selection of MGMT expressing cells or induction of the MGMT gene by alkylating agents. The p53 status was not significantly related to the MGMT expression level, although a trend for lower MGMT activity in p53 positively stained tumors was observed. Patients expressing MGMT activity of 30 fmol/mg protein in the pretreatment tumor had a significant better therapeutic response than patients expressing MGMT above this level, which was shown by Kaplan-Meyer curves and the recurrence free interval after primary tumor resection. In patients who received RT only, this correlation was not found. The data revealed a threshold of MGMT expression (30 fmol/mg protein) below which patients respond better to alkylating agents. Therefore, determination of MGMT activity in the primary tumor appears to be useful in predicting the outcome of GBM therapy. ' 2007 Wiley-Liss, Inc.Key words: DNA repair; alkyltransferase; MGMT; glioblastomas; drug resistance; temozolomide Despite the enormous progress in the treatment of various types of tumors, human gliomas still have a low curative response. In the therapy of gliomas, notably the most severe form glioblastoma multiforme (GBM, WHO grade IV), radiation therapy (RT) or RT concomitant with methylating agents such as temozolomide 1 is applied. Methylating and chloroethylating agents such as BCNU (carmustine), CCNU (lomustine) or ACNU (nimustine) are also administered during adjuvant therapy. 2 Unfortunately, only a minority of glioblastoma patients respond to temozolomide and chloroethylating nitrosoureas. A likely explanation for this is the development of either primary or acquired glioblastoma cell resistance that leads to protection of the tumor against alkylating drugs.Methylating and chloroethylating agents attack DNA at nucleophilic sites like the O 6 position of guanine, forming O 6 -alkylguanine. 3 This lesion is considered to be the major cause of mutations and malignant transformation induced by O 6 -alkylating agents. 4 It also provokes cell death by inducing apoptosis 5,6 and, therefore, is considered to be mainly responsible for the antineoplastic effect of O 6 -alkylating agents. O 6 -alkylguanine is repaired by the suicide DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) that transf...

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“…Many tumours express high levels of MGMT (Chen et al, 1992;Citron et al, 1994) and dose-limiting toxicities occur in the bone marrow, which expresses low levels of MGMT (Gerson et al, 1985). The inactivation of MGMT might thus be expected to increase the toxic effects of chemotherapy in tumours to a greater extent than in the bone marrow, and hence improve the therapeutic index.…”

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O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

et al. 2009

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We evaluated the pharmacodynamic effects of the O 6 -methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O 6 -methylguanine (O 6 -meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O 6 -meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O 6 -meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O 6 -meG in PBMC DNA during treatment.

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O⁶-Methylguanine-DNA Methyltransferase in Human Normal and Malignant Lung Tissues

Cited by 47 publications

References 6 publications

Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma

Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma

MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

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O6-Methylguanine-DNA Methyltransferase in Human Normal and Malignant Lung Tissues

Cited by 47 publications

References 6 publications

Inactivation of the DNA repair gene O6‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1‐DNA adducts and p53 mutation in hepatocellular carcinoma

Inactivation of the DNA repair gene O6‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1‐DNA adducts and p53 mutation in hepatocellular carcinoma

MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

Contact Info

Product

Resources

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O⁶-Methylguanine-DNA Methyltransferase in Human Normal and Malignant Lung Tissues

Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma

Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma