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Carcinogenesis, Vol. 20, No. 9, 1855-1862, September 1999
© 1999 Oxford University Press

Carcinogenesis

The cytotoxicity of DNA carboxymethylation and methylation by the model carboxymethylating agent azaserine in human cells

M. O'Driscoll, P. Macpherson, Yao-Zhong Xu1 and P. Karran2

Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts EN6 3LD and
1 CRC Nitrosamine-Induced Cancer Research Group, Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, UK

Carboxymethylating agents are potential sources of endogenous DNA damage that have been proposed as possible contributors to gastrointestinal carcinogenesis. The cytotoxicity of the model DNA carboxymethylating agent azaserine was investigated in human cells. Expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) did not affect sensitivity to the drug in two related Raji Burkitt's lymphoma cell lines. DNA mismatch repair-defective variants of Raji cells which display increased tolerance to DNA methylation damage were not selectively resistant to azaserine. Complementary results were obtained with a second carboxymethylating agent, potassium diazoacetate. In contrast, lymphoblastoid cell lines representative of each of the xeroderma pigmentosum complementation groups, including the variant, were all significantly more sensitive to azaserine than nucleotide excision repair-proficient cells. The hypersensitivity of XP cells was not due to systematic differences in the concentrations of intracellular thiol compounds or related thiol metabolizing enzymes. The data indicate that of the two types of potentially lethal DNA damage which azaserine introduces, carboxymethylated bases and O6-methylguanine, the former are repaired by nucleotide excision repair and are a more significant contributor to azaserine lethality in human cells.

Abbreviations: CDNB, 1-chloro-2,4-dinitrobenzene; CM, carboxymethyl; DON, 5'-diazo-6-oxonorleucine; GGT, {gamma}-glutamyl transpeptidase; GSH, reduced glutathione; GST, glutathione S-transferase; HPRT, hypoxanthine-guanine phosphoribosyltransferase; KDA, potassium diazoacetate; MGMT, O6-methylguanine-DNA methyltransferase; MMR, mismatch repair; MNNG, N-methyl-N'-nitro-N-nitrosoguanidine; MNU, N-methyl-N-nitrosourea; N7-CMGua, N7-carboxymethylguanine; N3-CMAde, N3-carboxymethyladenine; NER, nucleotide excision repair; O6-CMGua, O6-carboxymethylguanine; O6-meGua, O6-methylguanine; S6-CMGua, S6-carboxymethylthioguanine; TG, 6-thioguanine; XP, xeroderma pigmentosum.

2 To whom correspondence should be addressed Email: karran{at}icrf.icnet.uk


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E. Gottschalg, G. B. Scott, P. A. Burns, and D. E.G. Shuker
Potassium diazoacetate-induced p53 mutations in vitro in relation to formation of O6-carboxymethyl- and O6-methyl-2'-deoxyguanosine DNA adducts: relevance for gastrointestinal cancer
Carcinogenesis, February 1, 2007; 28(2): 356 - 362.
[Abstract] [Full Text] [PDF]


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