Mutagenic activity of cisplatin in the lacZ plasmid-based transgenic mouse model

Henriqueta Louro, Maria J. Silva, Maria G. Boavida

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Cis-diamminedichloroplatinum (II) (cisplatin) is a well characterized antitumor drug used for the treatment of a variety of human cancers. The cytotoxicity of cisplatin is mainly mediated through the formation of DNA adducts, which are also believed to be responsible for the secondary malignancies produced by the drug. The aim of this study was to determine the in vivo mutagenic activity of cisplatin in the lacZ plasmid-based transgenic mouse model. The mutant frequency (MF) and the spectrum of mutations induced by cisplatin in the mouse liver were analyzed and compared to controls. The mean MF in the lacZ gene was increased 2-fold in mice treated with a single 6 mg/kg body weight dose of cisplatin and sacrificed after 17 and 28 days (P = 0.00 1 and P < 0.0001). Restriction analysis and sequencing of mutant DNA showed that cisplatin was able to induce both large deletions and point mutations. A specific profile of base substitution and frameshift mutations was identified in treated mice, consisting primarily of G:C→A:T transitions at GpG and ApG sites, the preferential DNA binding sites of cisplatin, and single basepair deletions/insertions. The present results provide the first evidence that cisplatin has mutagenic activity in vivo and induces a characteristic pattern of mutations in the mouse liver. This mutagenicity may be responsible for its tumorigenic activity.

Original languageEnglish
Pages (from-to)283-291
Number of pages9
JournalEnvironmental And Molecular Mutagenesis
Volume40
Issue number4
DOIs
Publication statusPublished - 1 Dec 2002

Keywords

  • Cisplatin
  • In vivo
  • Mutant frequency
  • Mutation spectrum

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