The contribution of O6-methylguanine and methylphosphotriesters to the cytotoxicity of alkylating agents in mammalian cells.
A modified Escherichia coli ada+ gene which encodes methyltransferase active on O6-methylguanine, but not methylphosphotriester residues in DNA has been introduced by transfection into Chinese hamster ovary cells. Expression of the altered Ada protein in these cells conferred resistance to methylating agents. However, in two independently derived cell lines, the relation between enzyme activity and the degree of protection was not quantitative. The molecular nature of the Ada protein fragment produced differed between the two cell lines. In addition, cell lines exhibiting increased resistance to N-methyl-N'-nitro-N-nitrosoguanidine have been derived from a cell line expressing the Ada protein methylphosphotriester repair function. The resistant cell lines expressed elevated levels of methylphosphotriester repair protein. However, this enhanced DNA repair activity was not responsible for the observed resistance.
Hall
J
J
Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, UK.
Kataoka
H
H
Stephenson
C
C
Karran
P
P
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D004249:DNA Damage; D004260:DNA Repair; D004351:Drug Resistance; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D008741:Methyl Methanesulfonate; D008745:Methylation; D008769:Methylnitronitrosoguanidine; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010755:Organophosphates / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
D000477:Alkylating Agents; D010755:Organophosphates; D009943:Organophosphorus Compounds; D008769:Methylnitronitrosoguanidine; D006147:Guanine; C008449:O-(6)-methylguanine; D008741:Methyl Methanesulfonate; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase