The effectiveness of the O-6-alkylguanine-DNA alkyltransferase encoded by the ogt(ST) gene from S. typhimurium in protection against alkylating drugs, resistance to O-6-benzylguanine and sensitisation to dibromoalkane genotoxicity

Here we demonstrate that the Ogt(ST) from Salmonella typhimurium is a highl y efficient O-6-alkylguanine-DNA alkyltransferase (AGT) in affording protec tion against antitumour chloroethylating drugs (1,3-bis (2-chloroethyl)-1-n itrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)). In addition, OgtST is refractory to O-6-benzylguanine (BG) inactivation an d its expression provides only minor sensitisation to genotoxicity by envir onmental dibromoalkanes (DBE). No other of the assayed bacterial or human A GTs displayed such advantageous properties for chemoprotective gene therapy strategy. Our observations indicate that the OgtST AGT might be, under som e circumstances, of potential use to improve cancer chemotherapy. At least, its properties may provide further insight into the design of human AGT va riants that could be expressed in normal or tumour cells to provide either protection or ablation. (C) 2001 Elsevier Science B.V. All rights reserved.