Mechanisms of carcinogenesis induced by alkylating agents

Saffhill, Roy; Margison, Geoffrey P.; O’Connor, Peter J.

doi:10.1016/0304-419x(85)90009-5

Cited by 252 publications

(278 citation statements)

References 113 publications

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“…The detection of promutagenic lesions in GI tissue DNA samples in several regions of the world now provides a possible explanation for the presence in some GI tumours of activated ras genes (Bos, 1989) which could arise as a result of miscoding events due to the presence of alkylated bases during DNA synthesis (Saffhill et al, 1985). Although from these limited studies there is no direct indication of a relationship between cancer incidence and the extent of DNA alkylation it is anticipated that as data of this kind accumulate, it will not only be possible to define exposures to environmental sources of DNA damaging agents, but eventually to determine their importance and possibly also to begin to predict risk factors.…”

Section: Discussionmentioning

confidence: 99%

“…One such procedure is the use of radioimmunoassays (RIAs) to detect specific DNA lesions arising from exposure to alkylating agents. In the case of the simple alkylating agents, 13 products have been detected in DNA and of these, the promutagenic lesions 06-alkylguanine and 04-alkylthymine are thought to play a critical role in tumour initiation (Saffhill et al, 1985). A monoclonal antibody (McAb) specific for the detection of 06-methyl-2'-deoxyguanosine (06-MedG) (Wild et al, 1983;Myers et al, 1988;Saffhill et al, 1988a) has been used extensively to measure relatively high concentrations of 06-MeG in small samples of DNA extracted either from cell cultures (Boyle et al, 1986(Boyle et al, , 1987 or from mitochondrial DNA (Myers et al, 1988).…”

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confidence: 99%

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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: 99%

mentioning

confidence: 99%

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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“…The biological basis of organ-specific carcinogenesis is not yet fully understood, but several factors have been implicated; including distribution of the parent carcinogen, tissue-and cell-specific bioactivation, cell turnover and DNA repair (for review see refs [14][15][16][17][18][19][20]. The objective of the present study was to determine the extent to which aliphatic /V-nitrosomethylalkylamines methylate cellular DNA in various rat tissues.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation in rat tissues by a series of homologous aliphatic nitrosamines ranging from N-nitrosodimethylamine to N-nitrosomethyldodecylamine

et al. 1987

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Aliphatic iV-nitrosomethylalkylamines exhibit a remarkable organ specificity in rats, the principal targets for tumour induction being liver, oesophagus, urinary bladder and lung. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6 h survival) of each of 12 homologues, ranging from N-nitrosodimethyiamlne (Cl) to A4utrosomethyldodecylamine (C12). Methylpurines (7-and O*-methylguanine) were determined by cation exchange HPLC with fluorescence detection. Highest levels of hepatic DNA methylation were found with A'-nkrosodimethjiainine (Cl) and A'-nitrosornethylethylamine (C2), the most potent bepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length for C1-C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenkity, the butyl and pentyl derivatives (C4, C5) being most effective. In rat lung, the extent of DNA methylation was generally lower and there was no apparent correlation with carcinogenicity. Methylation of kidney DNA also decreased with increasing chain length and was only detectable for C1-C5. In urinary bladder DNA, methylpurines were below or close to the limit of detection. It is concluded that the initiation of malignant transformation by DNA methylation alone (through hydroxylation at the methylene a-carbon) could be operative for Cl in kidney and lung, for Cl and C2 in liver, and C3-C5 in oesophagus. For the higher homologues, the extent of DNA methylation seems insufficient to explain the complex pattern of tissue specificity, suggesting that DNA modification other than, or in addition to, methylation may be responsible. IntroductionEarly investigations by Druckrey and co-workers (1) on the carcinogenicity of asymmetric nitrosamines in rats revealed a high degree of organ-specificity. Short-chain N-nitrosomethylalkylamines (Cl, C2*) induced predominantly rumours of liver and lung whereas the higher asymmetric homologues (C3-C6) produced exclusively or preferentially oesophageal neoplasms.

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“…However, the continued transcription and translation of the ATase results in minimal cytotoxicity at this dose. Since both ogt and ada ATases are able to repair 06-MeG at the same rate (Wilkinson et al, 1989), whereas the ogt ATase repairs 04-MeT more efficiently than the ada enzyme (Wilkinson et al, 1989), the difference between LH2 and SB cell survival may be attributed to the more efficient repair of 04-MeT by the ogt enzyme, suggesting that even though 04-MeT constitutes only 0.7% of the total alkylated bases following MNU exposure (Saffhill et al, 1985) it could be a toxic lesion. However, unequivocal determination of 04-MeT-induced toxicity cannot be established without direct measurement of the adducts.…”

Section: Functional Activity Of the Ogt A Tase In Mammalian Cellsmentioning

confidence: 99%

Expression in mammalian cells of the Escherichia coli O6 alkylguanine-DNA-alkyltransferase gene ogt reduces the toxicity of alkylnitrosoureas

Harris

Margison²

1993

Br J Cancer

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V79 Chinese hamster cells expressing either the O6-alkylguanine-DNA-alkyltransferase (ATase) encoded by the E. coli ogt gene or a truncated version of the E. coli ada gene have been exposed to various alkylnitrosoureas to investigate the contribution of ATase repairable lesions to the toxicity of these compounds. Both ATases are able to repair O6-alkylguanine (O6-AlkG) and O4-alkylthymine (O4-AlkT) but the ogt ATase is more efficient in the repair of O4-methylthymine (O4-MeT) and higher alkyl derivatives of O6-AlkG than is the ada ATase. Expression of the ogt ATase provided greater protection against the toxic effects of the alkylating agents then the ada ATase particularly with N-ethyl-N-nitrosourea (ENU) and N-butyl-N-nitrosourea (BNU) to which the ada ATase expressing cells were as sensitive as parent vector transfected cells. Although ogt was expressed at slightly higher levels than the truncated ada in the transfected cells, this could not account for the differential protection observed. For-N-methyl-N-nitrosourea (MNU) the increased protection in ogt-transfected cells is consistent with O4-MeT acting as a toxic lesion. For the longer chain alkylating agents and chloroethylating agents, the protection afforded by the ogt protein may be a consequence of the more efficient repair of O6-AlkG, O4-AlkT or both of these lesions in comparison with the ada-encoded ATase. Images Figure 2 Figure 3

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Mechanisms of carcinogenesis induced by alkylating agents

Cited by 252 publications

References 113 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

DNA methylation in rat tissues by a series of homologous aliphatic nitrosamines ranging from N-nitrosodimethylamine to N-nitrosomethyldodecylamine

Expression in mammalian cells of the Escherichia coli O6 alkylguanine-DNA-alkyltransferase gene ogt reduces the toxicity of alkylnitrosoureas

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