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Assessment of the genotoxicity of the tyrosine kinase inhibitor imatinib mesylate in cultured fish and human cells.

Authors
  • Novak, Matjaž1
  • Žegura, Bojana2
  • Nunić, Jana3
  • Gajski, Goran4
  • Gerić, Marko5
  • Garaj-Vrhovac, Vera6
  • Filipič, Metka7
  • 1 Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia; Ecological Engineering Institute, Ljubljanska ulica 9, 2000 Maribor, Slovenia; Jozef Stefan International Postgraduate School, Jamova cesta 39, 1000 Ljubljana, Slovenia. Electronic address: [email protected] , (Slovenia)
  • 2 Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia. Electronic address: [email protected] , (Slovenia)
  • 3 Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia. Electronic address: [email protected] , (Slovenia)
  • 4 Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia. Electronic address: [email protected] , (Croatia)
  • 5 Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia. Electronic address: [email protected] , (Croatia)
  • 6 Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia. Electronic address: [email protected] , (Croatia)
  • 7 Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia. Electronic address: [email protected] , (Slovenia)
Type
Published Article
Journal
Mutation research
Publication Date
February 2017
Volume
814
Pages
14–21
Identifiers
DOI: 10.1016/j.mrgentox.2016.12.002
PMID: 28137363
Source
Medline
Keywords
License
Unknown

Abstract

The selective tyrosine kinase inhibitor imatinib mesylate (IM) is a widely used anticancer drug. Recent studies showing that IM can induce DNA and chromosomal damage in crustaceans and higher plants prompted us to re-examine its potential genotoxicity. IM was not mutagenic in the Ames assay (Salmonella typhimurium). Cytotoxicity and genotoxicity were evaluated in vitro in zebrafish (Danio rerio) liver (ZFL), human hepatoma (HepG2), and human peripheral blood lymphocyte (HPBL) cells. Genotoxicity was determined with the comet assay and with the cytokinesis-block micronucleus cytome assay. ZFL and HPBL cells showed comparable sensitivity to IM cytotoxicity, while HepG2 cells were less sensitive. At non-cytotoxic concentrations, IM induced DNA strand breaks in ZFL and HepG2 cells. An increase in the number of micronuclei was observed in ZFL and HPBL cells. In HPBLs, IM also induced an increase in the number of nucleoplasmic bridges and nuclear buds. Based on the data of the consumption of IM in European countries the predicted environmental concentrations (PEC) were calculated to be in the range between 3.3 and 5.0ng/L, which are several orders of magnitude lower from those that caused adverse effects in fish and human derived cells. However, based on the in vitro studies it is not possible to quantitatively predict the hazard for wildlife and humans, therefore further studies are warranted to explore the underlying molecular mechanisms of induced IM genotoxic effects as well as the studies of the occurrence of IM in the aquatic and occupational environment to establish the relevance of these observations for aquatic organisms and occupationally exposed personnel.

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