title: The hydroxyl epimer of doxorubicin controls the rate of formation of cytotoxic anthracycline-DNA adducts.
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.
authors.affiliation: La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Forrest
authors.forename: Lonnie P
authors.initials: LP
authors.lastname: Swift
authors.forename: Benny J
authors.initials: BJ
authors.lastname: Evison
authors.forename: Ada
authors.initials: A
authors.lastname: Rephaeli
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.forename: Don R
authors.initials: DR
authors.lastname: Phillips
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cutts
mesh_terms: D018943:Anthracyclines / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002241:Carbohydrates / Q000737:chemistry; D045744:Cell Line, Tumor; D004396:Coloring Agents; D003432:Cross-Linking Reagents; D003603:Cytotoxins / Q000378:metabolism*; D018736:DNA Adducts / Q000187:drug effects*; D015251:Epirubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005557:Formaldehyde / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D011419:Propidium; D012235:Rhodamines; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D002241:Carbohydrates; D004396:Coloring Agents; D003432:Cross-Linking Reagents; D003603:Cytotoxins; D018736:DNA Adducts; D012235:Rhodamines; C401833:tetramethylrhodamine methyl ester; D005557:Formaldehyde; D011419:Propidium; D015251:Epirubicin