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 highly efficient O(6)-alkylguanine-DNA alkyltransferase (AGT) in affording protection against antitumour chloroethylating drugs (1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)). In addition, Ogt(ST) is refractory to O(6)-benzylguanine (BG) inactivation and its expression provides only minor sensitisation to genotoxicity by environmental dibromoalkanes (DBE). No other of the assayed bacterial or human AGTs displayed such advantageous properties for chemoprotective gene therapy strategy. Our observations indicate that the Ogt(ST) AGT might be, under some circumstances, of potential use to improve cancer chemotherapy. At least, its properties may provide further insight into the design of human AGT variants that could be expressed in normal or tumour cells to provide either protection or ablation.
Abril
N
N
Departamento de Bioquímica y Biología Molecular, Campus de Rabanales, edificio C-6, planta 2a, 14071, Córdoba, Spain.
Luque-Romero
F L
FL
Yamada
M
M
Nohmi
T
T
Pueyo
C
C
D000473:Alkanes / Q000494:pharmacology; D000477:Alkylating Agents / Q000494:pharmacology; D000595:Amino Acid Sequence; D020134:Catalytic Domain / Q000235:genetics; D004249:DNA Damage; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D015946:Ethylene Dibromide / Q000494:pharmacology; D005798:Genes, Bacterial; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D000473:Alkanes; D000477:Alkylating Agents; D009153:Mutagens; C064976:O(6)-benzylguanine; D015946:Ethylene Dibromide; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase