Protein-associated DMA Breaks and DNA-Protein Cross-Links Caused by DMA Nonbinding Derivatives of Adriamycin in L1210 Cells1

The effects of Adriamycin derivatives on L1210 mouse leu kemia cells were studied with the DMA alkaline elution assay. The exposure of exponentially growing cells to approximately equitoxic concentrations of W-trifluoroacetyladriamycin-14-valerate (13.8 /ÕM) and its metabolites, /V-trifluoroacetyladriamycin (9.0 fiM) and N-trifluoroacetyladriamycinol (43.7 /IM), for 1 hr in vitro resulted in a high frequency of protein-associated DNA breaks and DNA-protein cross-links. These effects were com parable to those observed with Adriamycin (2.8 /ÕM)and with adriamycinol (26.9 ¿IM). In contrast to Adriamycin and its me tabolite adriamycinol, A/-trifluoroacetyladriamycin-14-valerate and its two major metabolites do not bind to DNA. Despite the absence of this direct interaction, A/-trifluoroacetyladriamycin14-valerate and its metabolites produce alterations in DNA comparable with the effects of intercalating agents. No evi dence for conversion of N-trifluoroacetyladriamycin-14-valer ate to Adriamycin or adriamycinol was found in L1210 cells. The similar effects on DNA macromolecules, observed between intercalating and non-DNA-binding anthracyclines, are con sistent with the concept that mechanisms other than direct interaction with DNA play a role in the toxic effects of these compounds.