Protein-associated DNA breaks and DNA-protein cross-links caused by DNA nonbinding derivatives of adriamycin in L1210 cells

Abstract

The effects of Adriamycin derivatives on L1210 mouse leukemia cells were studied with the DNA alkaline elution assay. The exposure of exponentially growing cells to approximately equitoxic concentrations of N-trifluoroacetyladriamycin-14-valerate (13.8 microM) and its metabolites, N-trifluoroacetyladriamycin (9.0 microM) and N-trifluoroacetyladriamycinol (43.7 microM), for 1 hr in vitro resulted in a high frequency of protein-associated DNA breaks and DNA-protein cross-links. These effects were comparable to those observed with Adriamycin (2.8 microM) and with adriamycinol (26.9 microM). In contrast to Adriamycin and its metabolite adriamycinol, N-trifluoroacetyladriamycin-14-valerate and its two major metabolites do not bind to DNA. Despite the absence of this direct interaction, N-trifluoroacetyladriamycin-14-valerate and its metabolites produce alterations in DNA comparable with the effects of intercalating agents. No evidence for conversion of N-trifluoroacetyladriamycin-14-valerate to Adriamycin or adriamycinol was found in L1210 cells. The similar effects on DNA macromolecules, observed between intercalating and non-DNA-binding anthracyclines, are consistent with the concept that mechanisms other than direct interaction with DNA play a role in the toxic effects of these compounds.