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 asub line (Raji TK^–) which is Mex^–. A reduction inO⁶-methylguanine (O⁶MeG)-DNA methyltransferase can be broughtabout by growing Raji cells in the presence of free O⁶MeG. Thedepletion in enzyme activity is specific and reversible; removalof O⁶MeG from the medium results in the restoration of methyltransferaseactivity within 4 h. Raji cells, in which methyltransferasehas been reduced by this treatment to below detectable levels,are not sensitised to killing by N-methyl-N'-nitro-N-nitrosoguanidineor the cross-linking nitrosoureas, 1, 3-bis(2-chloroethyl)-1-nitro-soureaand 1-(2-chloroethyl)-1-nitrosourea. This implies that adductsat the 0⁶ atom of guanine in DNA are not potentially cytotoxiclesions. Secondly, it suggests that a defect other than thelack of methyltransferase is responsible for the sensitivityof Mex^– cells to killing by alkylating agents.