Repair of O6-(2-chloroethyl)guanine mediates the biological effects of chloroethylnitrosoureas

Abstract

Chloroethylnitrosoureas (CENUs) are alkylating and crosslinking agents used for the treatment of human cancer; they are both mutagenic and carcinogenic. We compared the levels of induction of sister chromatid exchanges (SCEs) and the cytotoxicity of nitrosoureas that alkylate only with CENUs. CENUs are 200-fold more cytotoxic and induce SCEs with 45-fold greater efficiency than agents that do not crosslink; therefore, crosslinking is probably the most important molecular event that leads to cell death and induction of SCEs. The biological and biochemical properties of both human and rat brain tumor cells that are sensitive or resistant to the cytotoxic effects of CENUs have been investigated. CENUs induce SCEs in both sensitive and resistant cells, but to induce similar levels of SCEs, resistant cells must be treated with a 5- to 14-fold higher concentration of CENUs than are used to treat sensitive cells. Resistant cells have a higher cellular level of O6-methylguanine-DNA methyl transferase, increased repair of O6-methylguanine, and 50% fewer DNA interstrand crosslinks formed than do sensitive cells treated with the same concentration of CENU. Based on these findings, we propose that cellular resistance to the cytotoxic effects of CENUs is mediated by O6-methylguanine-DNA methyltransferase and that DNA repair may also modify the mutagenic and carcinogenic properties of CENUs.