The hydroxyl epimer of doxorubicin controls the rate of formation of cytotoxic anthracycline-DNA adducts

Epirubicin was developed as a semi-synthetic anthracycline derivative to circumvent the cardiotoxic limitations associated with the use of doxorubicin in the clinic. Anthracycline compounds have been demonstrated to form covalent drug–DNA adducts utilising endogenous and exogenous sources of formaldehyde; however, previous investigations of the formation of epirubicin-DNA adducts provide conflicting evidence for adduct formation. This work provides evidence that epirubicin acts to form drug–DNA adducts at physiologically relevant concentrations and demonstrates that the rate of formation of epirubicin-DNA adducts is slower than that observed for other anthracycline compounds, explaining why they are only detectable under defined experimental conditions. Formation of covalent epirubicin-DNA adducts improves the apoptotic profile of epirubicin and provides opportunities to overcome drug resistance and cardiotoxic limitations.