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Topoisomerase II mediated DNA-strand breakage by anthracyclines and n-alkylanthracyclines in V79 cells and in isolated pBR 322 DNA - its correlation to mutagenicity

: Reinke, H.; Boyens, M.; Arnold, H.-H.; Groth, G.; Marquardt, H.; Westendorf, J.

Naunyn-Schmiedebergs archives of pharmacology 339 (1989), pp.R24
ISSN: 0028-1298
ISSN: 1432-1912
Deutsche Gesellschaft für Pharmakologie und Toxikologie (Spring Meeting) <30, 1989, Mainz>
Conference Paper
Fraunhofer ITA ( ITEM) ()
anthracycline; DNA; genetic toxicology; genotoxicity; mutagenicity; pharmacology; toxicology

Since the genotoxicity of many antitumor agents is an important problem in modern cancer chemotherapy, we studied with anthracyclines the possibility that antitumor properties can be separated from genotoxicity. We previously demonstrated that N-alkylation of the primary amino group in the daunosamine moiety abolishes the genotoxicity of anthracyclines without influencing their antitumor properties. Anthracyclines are known to intercalate into the cellular DNA and DNA-strand breaks are induced by interaction of topoisomerase 2 with the intercalation complex. We now demonstrate that in V79 cells anthracyclines with a primary amino group induce DNA-strand breaks, whereas N-alkylated anthracyclines are inactive. These data are in excellent correlation with the mutagenicity of these compounds at the HGPRT genelocus, suggesting that the DNA-strand break induction is involved in the mutagenic activity. We also studied the induction of DNA-strand breaks in vitro with isolated calf thymus topo isomerase 2 and pBR 322 DNA. Contrary to the results in V79 cells, all investigated anthracyclines induced strand breaks. However, the pattern of fragments caused by mutagenic and non-mutagenic anthracyclines was different. Possibly, non-mutagenic N-alkylated and genotoxic non-alkylated anthracyclines intercalate into DNA with different base sequence preference.