title: Oxidative stress on cardiotoxicity after treatment with single and multiple doses of doxorubicin.
abstract: The mechanism of doxorubicin (DOX)-induced cardiotoxicity remains controversial. Wistar rats (n = 66) received DOX injections intraperitoneally and were randomly assigned to 2 experimental protocols: (1) rats were killed before (-24 h, n = 8) and 24 h after (+24 h, n = 8) a single dose of DOX (4 mg/kg body weight) to determine the DOX acute effect and (2) rats (n = 58) received 4 injections of DOX (4 mg/kg body weight/week) and were killed before the first injection (M0) and 1 week after each injection (M1, M2, M3, and M4) to determine the chronological effects. Animals used at M0 (n = 8) were also used at moment -24 h of acute study. Cardiac total antioxidant performance (TAP), DNA damage, and morphology analyses were carried out at each time point. Single dose of DOX was associated with increased cardiac disarrangement, necrosis, and DNA damage (strand breaks (SBs) and oxidized pyrimidines) and decreased TAP. The chronological study showed an effect of a cumulative dose on body weight (R = -0.99, p = 0.011), necrosis (R = 1.00, p = 0.004), TAP (R = 0.95, p = 0.049), and DNA SBs (R = -0.95, p = 0.049). DNA SBs damage was negatively associated with TAP (R = -0.98, p = 0.018), and necrosis (R = -0.97, p = 0.027). Our results suggest that oxidative damage is associated with acute cardiotoxicity induced by a single dose of DOX only. Increased resistance to the oxidative stress is plausible for the multiple dose of DOX. Thus, different mechanisms may be involved in acute toxicity versus chronic toxicity.
authors.affiliation: Department of Internal Medicine, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: M Pacifico de Freitas
authors.initials: MP
authors.lastname: Segredo
authors.affiliation: Department of Pathology, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: D M Favero
authors.initials: DM
authors.lastname: Salvadori
authors.affiliation: Department of Clinical Veterinary Medicine, Faculty of Veterinary Medicine, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: N S
authors.initials: NS
authors.lastname: Rocha
authors.affiliation: Department of Internal Medicine, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: F C Fontes
authors.initials: FC
authors.lastname: Moretto
authors.affiliation: Department of Internal Medicine, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: C R
authors.initials: CR
authors.lastname: Correa
authors.affiliation: Department of Pathology, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: E A
authors.initials: EA
authors.lastname: Camargo
authors.affiliation: Department of Pathology, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: D C
authors.initials: DC
authors.lastname: de Almeida
authors.affiliation: Department of Internal Medicine, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: R A Silva
authors.initials: RA
authors.lastname: Reis
authors.affiliation: Department of Pathology, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: C M Murbach
authors.initials: CM
authors.lastname: Freire
authors.affiliation: Department of Pathology, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: M G
authors.initials: MG
authors.lastname: Braz
authors.affiliation: United States Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Tang
authors.affiliation: Department of Internal Medicine, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: L S
authors.initials: LS
authors.lastname: Matsubara
authors.affiliation: Department of Internal Medicine, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil.
authors.forename: B B
authors.initials: BB
authors.lastname: Matsubara
authors.affiliation: Division of Food Bioscience, College of Biomedical and Health Sciences, Konkuk University, Chungju-si, South Korea.
authors.forename: K-J
authors.initials: KJ
authors.lastname: Yeum
authors.affiliation: Department of Internal Medicine, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, SP, Brazil ferreira@fmb.unesp.br.
authors.forename: A L A
authors.initials: AL
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism; D053960:DNA Breaks; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D004317:Doxorubicin
keywords: DNA damage; Doxorubicin; antioxidant capacity; heart; morphology; rat