Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes

Kawate, Hisaya; Sakumi, Kunihiko; Tsuzuki, Teruhisa; Nakatsuru, Yoko; Ishikawa, Takatoshi; Takahashi, Seiichi; Takano, Hiroshi; Noda, Tetsuo; Sekiguchi, Mutsuo

doi:10.1073/pnas.95.9.5116

Cited by 124 publications

(69 citation statements)

References 33 publications

(46 reference statements)

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“…Although tumours with methylated MGMT are more sensitive to the apoptotic effects of alkylating agents, it has been reported that Mgmt À/À mice with a loss of MLH1 expres- DNA repair genes in monoclonal gammopathies P Martin et al sion 45,46 are as resistant to alkylating drugs as are wild-type mice. Additionally, MMR-deficient cell lines display a mutator phenotype and resistance to several cytotoxic agents, including compounds widely used in cancer chemotherapy.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…29,30 Additionally, experiments with mice deficient in more than one pathway revealed that in primary hematopoietic cells the relative activity of different pathways is important for the cellular phenotype. 31 Thus, it is interesting to note that the reduced repair capacity For personal use only. on April 4, 2019. by guest www.bloodjournal.org From of CD34 ϩ cells observed in our studies most likely is not due to the low expression or activity of a single component of the complex DNA repair network (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of DNA repair in human CD34+progenitor cells corresponds to increased drug sensitivity and apoptotic response

Buschfort-Papewalis¹,

Möritz²,

Liedert³

et al. 2002

Blood

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Although DNA repair processes have been shown to considerably modulate the cytotoxic effects of alkylating agents, little information is available on the role of these mechanisms in chemotherapy-induced myelosuppression. Therefore, we have analyzed in detail the DNA repair capacity of primary human hematopoietic cells from cord blood (CB) or bone marrow (BM) by 2 functional assays, the immunocytologic assay (ICA) and singlecell gel electrophoresis (comet assay). Besides substantial interindividual differences, we consistently observed significantly lower repair capacity of CD34 ؉ cells in comparison to CD34 ؊ , CD19 ؉ , or CD33 ؉ cells of the same donor. After exposure to the alkylating agent ethylnitrosourea (EtNU), the comet assay displayed on average twice as many DNA single-strand breaks (SSBs) in CD34 ؉ cells and a tripled half-life of these lesions in comparison to corresponding CD34 ؊ cells. Similarly, reduced SSB repair activity in CD34 ؉ cells was detected following melphalan or cisplatin application. When specific antibodies were used to monitor DNA reaction products of these drugs, adduct levels were significantly higher and lesions persisted longer in the CD34 ؉ fraction. To assess the contribution of individual pathways to overall DNA repair, modulators blocking defined steps in repair processes were coapplied with alkylating drugs. Similar "modulation pattern" in corresponding CD34 ؉ and CD34 ؊ cell fractions indicated a generalized reduction in DNA repair capacity of CD34 ؉ cells, rather than deficiencies in a specific pathway. Because CD34 ؉ cells also displayed higher frequencies of apoptosis in response to melphalan or cisplatin, these findings may help to explain the myelosuppression after exposure to alkylating agents. (Blood. 2002;100:845-853)

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“…In the case of colorectal carcinoma, MGMT methylation does not confer sensitivity to the killing action of alkylating agents if the tumor is also MMR deficient (Kawate et al, 1998(Kawate et al, , 2000. This phenomenon occurs in approximately 10% of colon tumors and in this case the presence of simultaneous methylation-mediated silencing of hMLH1 and MGMT confers resistance to cell death and may increase the mutation rate of that neoplasm.…”

Section: Methylation-mediated Silencing Of Mgmt Marks Tumors Sensitivmentioning

confidence: 99%

Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

2004

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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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Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes

Cited by 124 publications

References 33 publications

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

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

Down-regulation of DNA repair in human CD34+progenitor cells corresponds to increased drug sensitivity and apoptotic response

Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

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