The cytotoxic and mutagenic effects of alkylating agents on human lymphoid cells are caused by different DNA lesions

Abstract

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-nitro-sourea and 1-(2-chloroethyl)-1-nitrosourea. This implies that adducts at the 0⁶ 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.