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

Robert A. Forrest, Lonnie P. Swift, Benny J. Evison, Ada Rephaeli, Abraham Nudelman, Don R. Phillips, Suzanne M. Cutts

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)809-816
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number3
DOIs
StatePublished - Mar 2013

Bibliographical note

Funding Information:
Acknowledgments This work was supported by an Australian Research Council Future Fellowship [SMC], the Marcus Center for Medicinal Chemistry [AN]; CPA Ronit Zilberfarb (Mehr) Z’’L, Israel Cancer Association Grant No 2012002 [AR] and an Australian Postgraduate Award [RAF].

Keywords

  • DNA damage
  • Drug-DNA adduct
  • Epirubicin
  • Formaldehyde
  • p53

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