Mutagenicity and genotoxicity of the major DNA adduct of the antitumor drug cis-diamminedichloroplatinum(II)

Lisa J N Bradley, Kevin J Yarema, Stephen J. Lippard, John M. Essigmann

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)982-988
Number of pages7
JournalBiochemistry®
Volume32
Issue number3
StatePublished - 1993
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

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