The toxicity and mutagenicity of the anti-tumour drug 5-aziridino-2,4-dinitrobenzamide (CB1954) is greatly reduced in a nitroreductase-deficient strain of E. coli.
In the 1970s it was shown that the monofunctional alkylating agent CB1954 (5-aziridino-2,4-dinitrobenzamide) kills the Walker rat carcinoma 256 in vivo and in vitro, but is inactive against several other tumours. In studies with bacteria, the large differences in survival in DNA-repair-proficient and deficient strains of Escherichia coli B treated with CB1954 were characteristic of a difunctional cross-linking agent. It was concluded that DNA was the only target large enough to receive significantly more than one lethal hit per molecule and that mono-alkylation alone could not account for the lethal effects of CB1954. In 1986 it was shown that CB1954 induced DNA interstrand cross-links in CB1954-sensitive cultured Walker 256 cells, but not in resistant Chinese hamster V79 cells, suggesting that the sensitivity of Walker cells results mainly from their activation of the drug to a difunctional agent by nitroreduction. To test this, we assayed the toxicity and mutagenicity of CB1954 in nitroreductase-plus and -minus strains of E. coli WP2uvrA. Agar-overlay assays showed that CB1954 was mutagenic to several strains of E. coli WP2, in a dose range 1-100 micrograms per plate, with slopes (mutants/nmol) of 7.1, 1.05 and 0.16 for WP2uvrA pKM101, WP2uvrA and WP2. Assays with nitrofurazone showed that these strains possessed nitroreductase activity. However, E. coli NFR-343, a nitrofurazone-resistant mutant of WP2uvrA which lacks nitroreductase activity was markedly less sensitive to the mutagenicity of CB1954, giving a mean slope of 0.12 compared with 1.15 for WP2uvrA. Aroclor-induced rat-liver S9 did not change these responses.(ABSTRACT TRUNCATED AT 250 WORDS)
Venitt
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Section of Chemical Carcinogenesis, Royal Cancer Hospital, Sutton, Surrey, UK.
Crofton-Sleigh
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology*; D001389:Azirines / Q000494:pharmacology*; D004260:DNA Repair; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D009601:Nitroreductases / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D001388:Aziridines; D001389:Azirines; D009153:Mutagens; C100099:tretazicar; D010088:Oxidoreductases; D009601:Nitroreductases