title: Dexrazoxane does not protect against doxorubicin-induced damage in young rats.
abstract: Doxorubicin (DOX), an anticancer drug, causes a dose-dependent cardiotoxicity. Some evidence suggests that female children have an increased risk for DOX-mediated cardiac damage. To determine whether the iron chelator dexrazoxane (DXR) could reduce DOX-induced cardiotoxicity in the young, we injected day 10 neonate female and male rat pups with a single dose of saline or DOX, DXR, or DXR + DOX (20:1). We followed body weight gain with growth, measured cardiac hypertrophy after a 2-wk swim exercise program, markers of apoptosis (Bcl-2, BAX, BNIP1, caspase 3 activation), oxidative stress (heme oxygenase 1, protein carbonyl levels), the chaperone protein clusterin, and the transcriptional activator early growth response gene-1 (Egr-1) in hearts of nonexercised and exercised rats on neonate day 38. All DOX-alone and DXR + DOX-treated rats showed decreased weight gain, with female rats affected earlier than male rats. DXR-alone, DOX-alone, and DXR + DOX-treated rats had an increased heart weight-to-body weight (heart wt/body wt) ratio after the exercise program with female rats showing the largest increase in heart wt/body wt. Drug-treated females also showed increased cardiac apoptosis, as measured by the increased expression of the proapoptotic proteins BAX and BNIP1 and the appearance of caspase 3 activation products, and oxidative stress, as measured by increased heme oxygenase 1 expression, and reduced Egr-1 and clusterin expression when compared with the similarly treated male rats. We conclude that DXR preinjection did not reduce DOX-induced noncardiac and cardiac damage and that young female rats were more susceptible to DXR and DOX toxicities than age-matched male rats.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Chemin Cote, St. Catherine, Montréal, Canada, H3T 1E2.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Héon
authors.forename: Martin
authors.initials: M
authors.lastname: Bernier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Servant
authors.forename: Stevan
authors.initials: S
authors.lastname: Dostanic
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wang
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Kirby
authors.forename: Lesley
authors.initials: L
authors.lastname: Alpert
authors.forename: Lorraine E
authors.initials: LE
authors.lastname: Chalifour
mesh_terms: D000367:Age Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001835:Body Weight; D002454:Cell Differentiation; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000494:pharmacology*; D033921:Vesicular Transport Proteins; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; C494828:Bax protein, rat; C485597:Bnip1 protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D033921:Vesicular Transport Proteins; D051028:bcl-2-Associated X Protein; D011929:Razoxane; D004317:Doxorubicin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1