The cytotoxic and mutagenic effects of alkylating agents on human lymphoid cells are caused by different DNA lesions.
The Burkitt's lymphoma cell line Raji has a Mex+ phenotype. It is more resistant to killing by alkylating agents than a sub line (Raji TK-) which is Mex-. A reduction in O6-methylguanine (O6MeG)-DNA methyltransferase can be brought about by growing Raji cells in the presence of free O6MeG. The depletion in enzyme activity is specific and reversible; removal of O6MeG from the medium results in the restoration of methyltransferase activity within 4 h. Raji cells, in which methyltransferase has been reduced by this treatment to below detectable levels, are not sensitised to killing by N-methyl-N'-nitro-N-nitrosoguanidine or the cross-linking nitrosoureas, 1,3-bis(2-chloroethyl)-1-nitrosourea and 1-(2-chloroethyl)-1-nitrosourea. This implies that adducts at the O6 atom of guanine in DNA are not potentially cytotoxic lesions. Secondly, it suggests that a defect other than the lack of methyltransferase is responsible for the sensitivity of Mex- cells to killing by alkylating agents.
D000477:Alkylating Agents / Q000633:toxicity*; D000478:Alkylation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects*; D008769:Methylnitronitrosoguanidine; D008780:Methyltransferases / Q000032:analysis / Q000378:metabolism; D009153:Mutagens; D019853:O(6)-Methylguanine-DNA Methyltransferase
D000477:Alkylating Agents; D009153:Mutagens; D008769:Methylnitronitrosoguanidine; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase