Mutagenicity and cross-linking activity of chloroalkylnitrosamines, possible new antitumor lead compounds.
The mutagenicity of chlorinated alpha-acetoxy nitrosamines was assayed using nine bacterial strains with various DNA repair abilities and the mechanism of their reaction with DNA was evaluated. Three alpha-acetoxy nitrosamines without a chloro group were used to investigate the effect of the chloro group on mutagenicity. Three nitrosamines having chloroethyl, chloropropyl and chlorobutyl groups were directly mutagenic in all tester strains used in this study, which showed that they damaged DNA in intact bacteria. Compared with Salmonella typhimurium TA1535, mutagenic activity was enhanced in ogt gene-deficient strains (YG7108 and YG7104), suggesting that an O(6)-alkylguanine adduct causes the mutation. The chlorinated nitrosamines showed stronger mutagenicity than non-chlorinated nitrosamines, indicating that alkylating activity was strengthened by the presence of a chloro group. The nitrosamines, especially the chloropropyl homolog, showed clear mutagenicity in the strains with an intact excision repair system, S.typhimurium TA92, TA1975 and G46. Further, chloropropyl and chlorobutyl homologs showed interstrand cross-linking activity towards plasmid DNA. These results suggest that some chlorinated nitrosamines can act on DNA to form DNA cross-links, as observed in antitumor chloroethylnitrosoureas. Environmental nitrosamines are usually dealt with as potential carcinogens, but introduction of a chloro group has added the possibility of in vivo cross-linking activity, which is a classical and essential mechanism for antitumor agents. Therefore, the novel chlorinated nitrosamines examined in this study are proposed as new bifunctional antitumor lead compounds.
Ishikawa
S
S
Kyoritsu College of Pharmacy, Shibakoen 1-5-30, Minato-ku, Tokyo 105-8512, Japan. ishikawa-st@kyoritsu-ph.ac.jp
Mochizuki
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects; D007854:Lead / Q000494:pharmacology*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D009602:Nitrosamines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D009153:Mutagens; D009602:Nitrosamines; D007854:Lead; D004247:DNA