title: Comparative cardiac toxicity of anthracyclines in vitro and in vivo in the mouse.
abstract: OBJECTIVE
  The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo.
  
  
  METHODS
  The cardiomyocytes were incubated with the three anthracyclines (1 µM) to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group) received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg) and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF), heart rate (HR) and cardiac output (CO) both prior to and 10 days after drug treatment.
  
  
  RESULTS
  In HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS), as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin.
  
  
  CONCLUSIONS
  This study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin.
authors.affiliation: Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Center, Richmond, Virginia Commonwealth University, Richmond, Virginia, USA. stoldo2@vcu.edu
authors.forename: Stefano
authors.initials: S
authors.lastname: Toldo
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Goehe
authors.forename: Marzia
authors.initials: M
authors.lastname: Lotrionte
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mezzaroma
authors.forename: Evan T
authors.initials: ET
authors.lastname: Sumner
authors.forename: Giuseppe G L
authors.initials: GG
authors.lastname: Biondi-Zoccai
authors.forename: Ignacio M
authors.initials: IM
authors.lastname: Seropian
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Van Tassell
authors.forename: Francesco
authors.initials: F
authors.lastname: Loperfido
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palazzoni
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.forename: David A
authors.initials: DA
authors.lastname: Gewirtz
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D004317:Doxorubicin