Further characterization of an E. coli strain resistant to the toxic and mutagenic action of cis-diamminedichloroplatinum(II).
An increased resistance to the toxic and mutagenic activity of the antitumor drug cis-diamminedichloroplatinum(II) (cis-DDP) in the E. coli strain BS21 compared to its wild-type parent, F26, has been reported. This resistance was neither due to different binding of cis-DDP to DNA nor to adaptive DNA repair (Germanier et al., 1984). In the present work, we found that mutation of the uvrA, recA and polA genes did not abolish the resistance of BS21 to the toxic action of cis-DDP. The lower mutability of BS21 was not influenced by the polA mutation, while uvrA greatly reduced and recA eliminated the mutagenic activity of cis-DDP in both strains. Treatment of BS21 and F26 with equal doses of cis-DDP produced the same initial number of platinum-DNA lesions. Little excision repair was detected in vivo in either strain during 6-h post-treatment incubation, the F26 strain being the most efficient of the two for this process. In contrast, F26 and BS21 were transformed identically by pBR322 DNA which had been treated with cis-DDP in vitro. Analysis of the platinum-DNA adducts which were formed between cis-DDP and salmon sperm DNA in the buffer conditions of this experiment suggests that plasmid DNA contains 80% monofunctional adducts and 20% bifunctional bis-guanine adducts. These data indicate that the selective toxicity and mutagenicity of these two strains in vivo are neither a result of different numbers of Pt-DNA lesions nor of their repair. The selectivity disappeared when the two bacterial strains were transformed by pBR322 DNA containing identical platinum-DNA lesions, suggesting that the biochemical events which process platinum-DNA lesions are the same in both strains. Hence, it appears that cis-DDP may form qualitatively different platinum-DNA adducts in the BS21 and F26 strains which are responsible for the different toxicity and mutagenicity.
D002945:Cisplatin / Q000633:toxicity*; D004260:DNA Repair; D004269:DNA, Bacterial / Q000378:metabolism; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D005798:Genes, Bacterial; D009153:Mutagens; D009154:Mutation; D010957:Plasmids; D010984:Platinum / Q000378:metabolism; D014169:Transformation, Bacterial
D004269:DNA, Bacterial; D009153:Mutagens; D010984:Platinum; D002945:Cisplatin