Microbial mutagenicity of chlorambucil, its half-mustard and mitomycin C: a modified screening strategy for genetic toxicology of bis-alkylating anti-tumour drugs.
Early assessment of the genetic toxicology of anti-tumour drugs often employs microbial assays, particularly a group of specially developed Salmonella typhimurium strains (uvrB-) which are DNA repair-deficient due to a defective uvrB gene. While such strains are more sensitive than the wild-type to the mutagenic effects of many classes of compound, the DNA cross-linking agent chlorambucil (which is a known human carcinogen) has been shown to be toxic but non-mutagenic in this assay. The mutagenic activities of chlorambucil, its half-mustard analogue and another cross-linking agent (mitomycin C) were thus evaluated in a DNA-proficient strain of the yeast Saccharomyces cerevisiae and also in two isogenic sets of four S. typhimurium strains differing in uvrB gene and plasmid pKM101 presence. In yeast, all three compounds were effective mutagens and recombinogens, while in bacteria the two cross-linking agents were significantly mutagenic in the uvrB+ (DNA repair-proficient) but not in the uvrB- strains. By comparison, the half-mustard was mutagenic in both the uvrB- and uvrB+ strains. This work suggests that it is unwise to rely on results from the commonly used S. typhimurium bacterial strains for evaluating the mutagenicity of DNA cross-linking agents destined as clinical anti-tumour drugs. The use of yeast plus at least one of the sets of four strains employed in this study would provide information more directly relevant to mammalian cells, which are DNA repair-proficient. In addition, a comparison of the patterns of bacterial mutagenicity and toxicity provides evidence for the mode of action (DNA cross-linking or monoadduct formation) of compounds within a series.
D000477:Alkylating Agents / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002699:Chlorambucil / Q000031:analogs & derivatives / Q000633:toxicity*; D016685:Mitomycin; D008937:Mitomycins / Q000633:toxicity*; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000235:genetics; D012486:Salmonella typhimurium / Q000235:genetics; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D008937:Mitomycins; D002699:Chlorambucil; D016685:Mitomycin