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.