The cytotoxicity of DNA carboxymethylation and methylation by the model carboxymethylating agent azaserine in human cells.
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 O(6)-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 O(6)-methylguanine, the former are repaired by nucleotide excision repair and are a more significant contributor to azaserine lethality in human cells.
O'Driscoll
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Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, London, UK.
Macpherson
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P
Xu
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YZ
Karran
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P
D000225:Adenine / Q000031:analogs & derivatives / Q000032:analysis; D000477:Alkylating Agents / Q000633:toxicity*; D001377:Azaserine / Q000633:toxicity*; D001391:Azo Compounds / Q000633:toxicity*; D002051:Burkitt Lymphoma / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis; D004249:DNA Damage; D019175:DNA Methylation; D004351:Drug Resistance; D004790:Enzyme Induction; D005816:Genetic Complementation Test; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008745:Methylation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014983:Xeroderma Pigmentosum / Q000145:classification / Q000235:genetics / Q000473:pathology
D000477:Alkylating Agents; D001391:Azo Compounds; D002273:Carcinogens; D018736:DNA Adducts; C121410:N3-carboxymethyladenine; C121409:O(6)-carboxymethyguanine; C120482:potassium diazoacetate; D006147:Guanine; C034100:7-carboxymethylguanine; D001377:Azaserine; C008449:O-(6)-methylguanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000225:Adenine; D005998:Glycine