Mutagenicity and genotoxicity of the major DNA adduct of the antitumor drug cis-diamminedichloroplatinum(II).
The mutagenicity and genotoxicity of cis-[Pt(NH3)2[d(GpG)-N7(1),-N7(2)]] (G*G*), the major DNA adduct of the antitumor drug cisplatin, has been investigated in Escherichia coli. A duplex bacteriophage M13 genome was constructed to contain the G*G* adduct at a specific site in the (-) strand. The singly platinated duplex genome exhibited a survival of 22% relative to that of the unplatinated control genomes, and this value rose to 38% in cells treated with ultraviolet light to induce the SOS response. Singly platinated single-stranded genomes were also produced. Replication of the single- and double-stranded genomes in vivo yielded SOS-dependent, targeted mutations at frequencies of 1.3% and 0.16%, respectively. The mutagenic specificity of G*G* in both single- and double-stranded DNA was striking in that 80-90% of the mutations occurred at the 5'-platinated G. Approximately 80% of the mutations were G-->T transversions at that site. A model of mutagenesis is presented to explain this mutational specificity with respect to current understanding of platinum-DNA adduct structure.
Bradley
L J
LJ
Department of Chemistry, Whitaker College of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge 02139.
Yarema
K J
KJ
Lippard
S J
SJ
Essigmann
J M
JM
D017104:Bacteriophage M13 / Q000187:drug effects* / Q000235:genetics; D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology* / Q000633:toxicity; D004247:DNA / Q000494:pharmacology* / Q000633:toxicity; D018736:DNA Adducts; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000235:genetics; D004279:DNA, Viral / Q000187:drug effects* / Q000235:genetics; D004926:Escherichia coli / Q000502:physiology / Q000528:radiation effects; D016679:Genome, Viral; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000187:drug effects*; D016297:Mutagenesis, Site-Directed / Q000187:drug effects; D013014:SOS Response, Genetics; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
D018736:DNA Adducts; D004277:DNA, Single-Stranded; D004279:DNA, Viral; C057270:cisplatin-DNA adduct; D004247:DNA; D002945:Cisplatin