The role of O6-methylguanine-DNA methyltransferase in cell survival, mutagenesis and carcinogenesis

Yarosh, Daniel B.

doi:10.1016/0167-8817(85)90034-3

Cited by 177 publications

(75 citation statements)

References 119 publications

(164 reference statements)

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“…Loss of the capacity to metabolise carcinogens has been observed in animal tumours Cameron et al, 1976) and an increased capacity for DNA turnover or DNA repair could be responsible. There are, however, no strong precedents for the latter interpretation and on the contrary, reduced repair of 06-MeG has been observed in about 20% of established tumour cell lines (Yarosh, 1985). In vivo, a wide range of DNA-alkyltransferase activities was found in human neural tumours (Wiestler et al, 1984).…”

Section: Discussionmentioning

confidence: 97%

The detection of alkylation damage in the DNA of human gastrointestinal tissues

Hall

Badawi²,

O’Connor³

et al. 1991

Br J Cancer

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Summary Damage arising from putative environmental sources has been found in the DNA of the gastric and colorectal mucosae of patients presenting with gastrointestinal disorders from the South Manchester area.06-Methylguanine (06-MeG) in the range 0.010->0.300timolesmole-' adenine was heterogeneously distributed both between and within individuals. The pattern of alkylation of tissue DNA appears to differ when comparison is made between gastric and colorectal samples. Most of the gastric tumour DNA samples were alkylated (5/6; 0.087 + 0.097), whereas the DNA of the associated mucosa was alkylated less frequently (2/7) and to a lesser extent; (0.017 ± 0.030; P = 0.07). Conversely, colorectal tumour DNA was alkylated infrequently (1/7) and to a lower extent (0.003 ± 0.007) than the DNA of the adjacent mucosa (8/10 samples alkylated with a mean of 0.083 + 0.106; P = <0.01), or indeed of any other tissue. Although increased levels of DNA damage in tissue associated with malignant disease have been indicated by independent studies of DNA damage at other cancer sites, significant differences were not observed in the present report, neither was there any suggestion of a relationship with smoking or alcohol consumption.The data provided by this report indicate that exposure to putative environmental alkylating agents occurs in the UK at levels comparable to those previously detected in areas of higher cancer risk. Although we cannot determine the extent to which this DNA damage is attributable to normal background exposures, it is evident that the alkylation of tissue DNA occurs and is not uniform. In conjunction with other reports, therefore these differences may begin to provide indications of mechanisms that could be of relevance in the aetiology of gastrointestinal cancers.

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Section: Discussionmentioning

confidence: 97%

The detection of alkylation damage in the DNA of human gastrointestinal tissues

Hall

Badawi²,

O’Connor³

et al. 1991

Br J Cancer

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“…Of base alkylations, the most significant pre-mutagenic lesions induced by ENU are O 6 -ethylguanine, O 2 -ethylthymine, and O 4 -ethylthymine. The first of these adducts is, however, readily repaired by O 6 -alkylguanine transferase [38] and by nucleotide excision repair, while the other two types of adducts have been reported not to be removed by either mechanism [20]. This leads to the greater proportion of mutations in A-T than G-C base pairs that has been reported for ENU-induced SG mutations recovered in the specific-locus test [4,5,8] or in transgenic mice, both λlacZ [20] and λlacI [39].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the genetic effects of equimolar doses of ENU and MNU: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia

Russell

Hunsicker

Russell

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Mutagenic, reproductive, and toxicity effects of two closely related chemicals, ethylnitrosourea (ENU) and methylnitrosourea (MNU), were compared at equimolar and near-equimolar doses in the mouse specific-locus test in a screen of all stages of spermatogenesis and spermiogenesis. In stemcell spermatogonia (SG), ENU is more than an order of magnitude more mutagenic than MNU. During post-SG stages, both chemicals exhibit high peaks in mutation yield when differentiating spermatogonia (DG) and preleptotene spermatocytes are exposed. The mutation frequency induced by 75 mg MNU/kg during this peak interval is, to date, the highest induced by any single-exposure mutagenic treatment -chemical or radiation -that allows survival of the exposed animal and its germ cells, producing an estimated 10 new mutations per genome. There is thus a vast difference between stem cell and differentiating spermatogonia in their sensitivity to MNU, but little difference between these stages in their sensitivity to ENU.During stages following meiotic metaphase, the highest mutation yield is obtained from exposed spermatids, but for both chemicals, that yield is less than one-quarter that obtained from the peak interval. Large-lesion (LL) mutations were induced only in spermatids. Although only a few of the remaining mutations were analyzed molecularly, there is considerable evidence from recent molecular characterizations of the marker genes and their flanking chromosomal regions that most, if not all, mutations induced during the peak-sensitive period did not involve lesions outside the marked loci. Both ENU and MNU treatments of post-SG stages yielded significant numbers of mutants that were recovered as mosaics, with the proportion being higher for ENU than for MNU.Comparing the chemicals for the endpoints studied and additional ones (e.g., chromosome aberrations, toxicity to germ cells and to animals, teratogenicity) revealed that while MNU is generally more effective, the opposite is true when the target cells are SG.

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“…Their cytotoxicity, mutagenicity, carcinogenicity and clastogenicity has been shown to be due in large part to their ability to alkylate DNA and in particular to form O 6 -alkylguanine (O 6 -alkG). Cells, both normal and neoplastic, possess the ability to repair this adduct via a single step reaction involving O 6 -alkylguanine-DNA alkyltransferase (ATase) (Yarosh, 1985;Pegg and Dolan, 1987;Margison and O'Connor, 1990;Pegg, 1990;Pegg and Byers, 1992). ATase catalyses the transfer of the alkyl group from DNA to a cysteine acceptor site within the protein, resulting in the auto-inactivation of the ATase.…”

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confidence: 99%

Influence of O6-benzylguanine on the anti-tumour activity and normal tissue toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea and molecular combinations of 5-fluorouracil and 2-chloroethyl-1-nitrosourea in mice

et al. 1999

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Summary Previous studies have demonstrated that novel molecular combinations of 5-fluorouracil (5FU) and 2-chloroethyl-1-nitrosourea (CNU) have good preclinical activity and may exert less myelotoxicity than the clinically used nitrosoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study examined the effect of O 6 -alkylguanine-DNA-alkyltransferase (ATase) depletion by the pseudosubstrate O 6 -benzylguanine (BG) on the anti-tumour activity and normal tissue toxicity in mice of three such molecular combinations, in comparison with BCNU. When used as single agents at their maximum tolerated dose, all three novel compounds produced a significant growth retardation of BCNU-resistant murine colon and human breast xenografts. This in vivo anti-tumour effect was potentiated by BG, but was accompanied by severe myelotoxicity as judged by spleen colony forming assays. However, while tumour resistance to BCNU was overcome using BG, this was at the expense of enhanced bone marrow, gut and liver toxicity. Therefore, although this ATase-depletion approach resulted in improved anti-tumour activity for all three 5-FU:CNU molecular combinations, the potentiated toxicities in already dose-limiting tissues indicate that these types of agents offer no therapeutic advantage over BCNU when they are used together with BG.Keywords: O 6 -benzylguanine, nitrosoureas, anti-tumour, tissue toxicity, mouse 1332British Journal of Cancer (1999) 79(9/10), 1332-1339 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 6 March 1998 Revised 16 September 1998 Accepted 22 September 1998 Correspondence to: MC Bibby Anti-tumour effect of BG with BCNU or three novel nitrosoureas 1333British Journal of Cancer (1999) 79(9/10), 1332-1339 © Cancer Research Campaign 1999 linear pseudo-sugar fragment linking the CNU and the 5FU by the normal N 1 has been greatly simplified, the closely-related B.3996 (McElhinney et al, 1989b), containing sulphur in place of the normal sugar oxygen and an N 3 link to the pyrimidine ring and B.4152 (Loadman et al, 1996) which retains all four carbon atoms of the furanose skeleton, although lacking the usual sugar hydroxyl groups. Previous studies have shown B.4152 to be relatively marrow-sparing in a mouse in vivo model (Loadman et al, 1996).Here we report the results of a study designed to determine the capacity of BG to potentiate the anti-tumour activity of B.3995, B.3996 and B.4152, in comparison to BCNU, and to investigate the extent to which these molecular combinations are sparing to normal tissues, particularly the bone marrow. MATERIALS AND METHODS AnimalsPure strain NMRI mice from an inbred colony were purchased from B&K Universal Ltd, Hull, UK. NCR/Nu mice were obtained from the National Cancer Institute, Frederick, Maryland, USA. They were fed with a pellet diet (CRM, Special Diets Services, Witham, Essex, UK) and water ad libitum. Nude mice were housed in isolation cabinets. All mice had reached a minimum age of 8 weeks before use. Animal experiments were conducted in compliance wit...

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The role of O6-methylguanine-DNA methyltransferase in cell survival, mutagenesis and carcinogenesis

Cited by 177 publications

References 119 publications

The detection of alkylation damage in the DNA of human gastrointestinal tissues

The detection of alkylation damage in the DNA of human gastrointestinal tissues

Comparison of the genetic effects of equimolar doses of ENU and MNU: While the chemicals differ dramatically in their mutagenicity in stem-cell spermatogonia, both elicit very high mutation rates in differentiating spermatogonia

Influence of O6-benzylguanine on the anti-tumour activity and normal tissue toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea and molecular combinations of 5-fluorouracil and 2-chloroethyl-1-nitrosourea in mice

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