Exposure of HeLa cells to 0⁶-alkylguanines increases sensitivity to the cytotoxic effects of alkylating agents

Exposure of HeLa S3 cells to 0.4mM 0⁶-methylguanine or 0⁶-n-butylguanine for 24 h led to a substantial decrease in the activity of 0⁶-alkylguanine-DNA alkyltransferase. Such pretreatment caused a marked increase in the sensitivity of the cells to the cytotoxic effects of the cross-linking alkylating agent 1-(2-chloroethyl)-1-nitroso-3-cyclohexylurea and a smaller increase in the sensitivity to N-methyl-N′-nitro-N-nitrosoguanidine. These results indicate that the repair of DNA by the alkyltransferase plays an important role in the protection of cells from the cytotoxic effects of certain alkylating agents particularly those such as 1-(2-chloroethyl)-1-nitroso-3-cyclohexylurea which ultimately lead to the formation of lethal interstrand cross-links.