Role of O6-Alkylguanine-DNA Alkyltransferase in Protecting against 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)-Induced

O6-alkylguanine-DNA alkyltransferase (AGT) protects from the mutagenic and toxic lesions induced by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and in many tumors, AGT overex-pression provides a means of resistance. To circumvent this, O6-benzylguanine, an inactivator of AGT, has been developed and is currently in clinical development with BCNU; however, the potential long-term toxicities associated with this treatment are unknown. With the inactivation of AGT by O6-benzylgua-nine, a higher number of toxic and mutagenic O6-alkylguanine lesions introduced by methylating or chloroethylating agents would be expected. In this study, cohorts of mice were treated with vehicle, O6-benzylguanine (30 mg/kg), BCNU alone (low dose of 15 mg/kg or high dose of 50 mg/kg), or O6-benzylgua-nine (30 mg/kg) plus BCNU (15 mg/kg) and followed for 1