Mutagenic and genotoxic effects of DNA adducts formed by the anticancer drug cis-diamminedichloroplatinum(II)

Kevin J Yarema, Stephen J. Lippard, John M. Essigmann

Research output: Contribution to journalArticle

Abstract

The toxicity and mutagenicity of three DNA adducts formed by the anticancer drug cis-diamminedichloroplatinum(II) (cis-DDP or cisplatin) were investigated in Escherichia coli. The adducts studied were cis-[Pt(NH3)2{d(GpG)}] (G*G*), cis-[Pt(NH3)2{d(ApG)}] (A*G*) and cis-[Pt(NH3)2{d(GpTpG)}] (G*TG*), which collectively represent ∼95% of the DNA adducts reported to form when the drug damages DNA. Oligonucleotide 24-mers containing each adduct were positioned at a known site within the viral strand of single stranded M13mp7L2 bacteriophage DNA. Following transfection into E.coli DL7 cells, the genomes containing the G*G*, A*G* and G*TG* adducts had survival levels of 5.2 ± 1.2, 22 ± 2.6 and 14 ± 2.5% respectively, compared to unmodified genomes. Upon SOS induction, the survival of genomes containing the G*G* and A*G* adducts increased to 31 ± 5.4 and 32 ± 4.9% respectively. Survival of the genome containing the G*TG* adduct did not increase upon SOS induction. In SOS induced cells, the G*G* and A*G* adducts gave rise predominantly to G→T and A→T transversions respectively, targeted to the 5′ modified base. In addition, A→G transitions were detected for the A*G* adduct and low levels of tandem mutations at the 5′ modified base as well as the adjacent 5′ base were also observed for both adducts. The A*G* adduct was more mutagenic than the G*G* adduct, with a mutation frequency of 6% compared to 1.4% for the latter adduct. No cis-{Pt(NH3)2}2+ intrastrand crosslink-specific mutations were observed for the G*TG* adduct.

Original languageEnglish (US)
Pages (from-to)4066-4072
Number of pages7
JournalNucleic Acids Research
Volume23
Issue number20
StatePublished - Oct 25 1995
Externally publishedYes

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DNA Adducts
Cisplatin
Drugs
Genome
Genes
Mutation
Pharmaceutical Preparations
Escherichia coli
Escherichia Coli
Proof by induction
DNA
Gastrin-Secreting Cells
Bacteriophages
Oligonucleotides
Cell
Mutation Rate
Toxicity
DNA Damage
Transfection
Adjacent

ASJC Scopus subject areas

  • Genetics
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Health, Toxicology and Mutagenesis
  • Toxicology
  • Genetics(clinical)

Cite this

Mutagenic and genotoxic effects of DNA adducts formed by the anticancer drug cis-diamminedichloroplatinum(II). / Yarema, Kevin J; Lippard, Stephen J.; Essigmann, John M.

In: Nucleic Acids Research, Vol. 23, No. 20, 25.10.1995, p. 4066-4072.

Research output: Contribution to journalArticle

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abstract = "The toxicity and mutagenicity of three DNA adducts formed by the anticancer drug cis-diamminedichloroplatinum(II) (cis-DDP or cisplatin) were investigated in Escherichia coli. The adducts studied were cis-[Pt(NH3)2{d(GpG)}] (G*G*), cis-[Pt(NH3)2{d(ApG)}] (A*G*) and cis-[Pt(NH3)2{d(GpTpG)}] (G*TG*), which collectively represent ∼95{\%} of the DNA adducts reported to form when the drug damages DNA. Oligonucleotide 24-mers containing each adduct were positioned at a known site within the viral strand of single stranded M13mp7L2 bacteriophage DNA. Following transfection into E.coli DL7 cells, the genomes containing the G*G*, A*G* and G*TG* adducts had survival levels of 5.2 ± 1.2, 22 ± 2.6 and 14 ± 2.5{\%} respectively, compared to unmodified genomes. Upon SOS induction, the survival of genomes containing the G*G* and A*G* adducts increased to 31 ± 5.4 and 32 ± 4.9{\%} respectively. Survival of the genome containing the G*TG* adduct did not increase upon SOS induction. In SOS induced cells, the G*G* and A*G* adducts gave rise predominantly to G→T and A→T transversions respectively, targeted to the 5′ modified base. In addition, A→G transitions were detected for the A*G* adduct and low levels of tandem mutations at the 5′ modified base as well as the adjacent 5′ base were also observed for both adducts. The A*G* adduct was more mutagenic than the G*G* adduct, with a mutation frequency of 6{\%} compared to 1.4{\%} for the latter adduct. No cis-{Pt(NH3)2}2+ intrastrand crosslink-specific mutations were observed for the G*TG* adduct.",
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