title: Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits.
abstract: Despite incomplete understanding to its mechanism of action, dexrazoxane (DEX) is still the only clearly effective cardioprotectant against chronic anthracycline (ANT) cardiotoxicity. However, its clinical use is currently restricted to patients exceeding significant ANT cumulative dose (300mg/m(2)), although each ANT cycle may induce certain potentially irreversible myocardial damage. Therefore, the aim of this study was to compare early and delayed DEX intervention against chronic ANT cardiotoxicity and study the molecular events involved. The cardiotoxicity was induced in rabbits with daunorubicin (DAU; 3mg/kg/week for 10 weeks); DEX (60mg/kg) was administered either before the 1st or 7th DAU dose (i.e. after ≈300mg/m(2) cumulative dose). While both DEX administration schedules prevented DAU-induced premature deaths and severe congestive heart failure, only the early intervention completely prevented the left ventricular dysfunction, myocardial morphological changes and mitochondrial damage. Further molecular analyses did not support the assumption that DEX cardioprotection is based and directly proportional to protection from DAU-induced oxidative damage and/or deletions in mtDNA. Nevertheless, DAU induced significant up-regulation of heme oxygenase 1 pathway while heme synthesis was inversely regulated and both changes were schedule-of-administration preventable by DEX. Early and delayed DEX interventions also differed in ability to prevent DAU-induced down-regulation of expression of mitochondrial proteins encoded by both nuclear and mitochondrial genome. Hence, the present functional, morphological as well as the molecular data highlights the enormous cardioprotective effects of DEX and provides novel insights into the molecular events involved. Furthermore, the data suggests that currently recommended delayed intervention may not be able to take advantage of the full cardioprotective potential of the drug.
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, Hradec Králové 500 38, Czech Republic.
authors.forename: Eduard
authors.initials: E
authors.lastname: Jirkovský
authors.forename: Olga
authors.initials: O
authors.lastname: Lenčová-Popelová
authors.forename: Miloš
authors.initials: M
authors.lastname: Hroch
authors.forename: Michaela
authors.initials: M
authors.lastname: Adamcová
authors.forename: Yvona
authors.initials: Y
authors.lastname: Mazurová
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Vávrová
authors.forename: Stanislav
authors.initials: S
authors.lastname: Mičuda
authors.forename: Tomáš
authors.initials: T
authors.lastname: Šimůnek
authors.forename: Vladimír
authors.initials: V
authors.lastname: Geršl
authors.forename: Martin
authors.initials: M
authors.lastname: Štěrba
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003630:Daunorubicin / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D011817:Rabbits; D011929:Razoxane / Q000008:administration & dosage*; D020107:Troponin T / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D051267:NF-E2-Related Factor 2; D020107:Troponin T; D011929:Razoxane; D002950:Citrate (si)-Synthase; D003630:Daunorubicin
keywords: 5-aminolevulinate synthase 1; ALAS1; ANT; Anthracycline; BVR A; COX1, COX4; Cardioprotection; Cardiotoxicity; DAU; DEX; Dexrazoxane; FU; GSH; GSSG; HIF1α; HO1; Heart failure; LV FS; MDA; Mechanisms; MnSOD; NAD(P)H dehydrogenase [quinone] 1; NADPH oxidases 2 and 4; ND1; ND4 mitochondrial genome-encoded complex I subunits; NDUFS2; NOX2, NOX4; NQO1; NRF1; Nrf2; PRDX3; TFAM; anthracycline; biliverdin reductase A; daunorubicin; dexrazoxane; heme oxygenase 1; hypoxia-inducible factor 1α; left ventricular fractional shortening; malondialdehyde; mitochondrial DNA; mitochondrial and nuclear genome-encoded complex IV subunits, respectively; mitochondrial superoxide dismutase; mitochondrial transcription factor A.; mtDNA; nDNA; nuclear DNA; nuclear factor erythroid 2-related factor 2; nuclear genome-encoded complex I subunit; nuclear respiratory factor 1; oxidized glutathione; peroxiredoxin 3; post-treatment follow up; reduced glutathione