title: The impact of doxorubicin and dexrazoxane injection of prepubertal female rats on pregnancy outcome and cardiac function postpartum.
abstract: Childhood cancer survivors can develop significant cardiac dysfunction in adulthood as a consequence of their cancer treatment. Studies have linked heart failure during pregnancy to childhood doxorubicin (DOX) exposure. We hypothesized that DOX injection would reduce cardiac function peripartum and that DOX-treated dams would show greater cardiac remodeling postweaning. Weanling female Sprague-Dawley rats were injected with phospate-buffered saline, DOX (3 mg/kg), or DOX plus the cardioprotectant dexrazoxane (DEX; 60 mg/kg) and followed for 2 pregnancies. DOX and DOX:DEX dams were fertile, but had fewer pups and more pup losses. Echocardiography, 1-day postpartum after each pregnancy, revealed greater increases in cardiac mass and eccentric hypertrophy in DOX-treated dams and early dilation in DOX:DEX dams. The expression of calcium homeostasis proteins can change after DOX treatment and cardiac remodeling. SERCA2a expression did not change. Reductions in phospholamban and phospho-serine 16-specific phospholamban expression in DOX dams were not relieved by DEX coinjection. DOX binds and inactivates calsequestrin 2 expression so increased calsequestrin 2 expression in DOX:DEX-treated dams suggests some DEX compensation. The eccentric hypertrophy and dilation development, despite compensatory changes in proteins controlling calcium cycling, suggest DOX damage with repeat pregnancy that was not alleviated fully by DEX.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, QC H3T 1E2, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Calvé
authors.forename: William
authors.initials: W
authors.lastname: Noiles
authors.forename: Igal A
authors.initials: IA
authors.lastname: Sebag
authors.forename: Lorraine E
authors.initials: LE
authors.lastname: Chalifour
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D002155:Calsequestrin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D054715:Cardiotoxins / Q000009:adverse effects / Q000037:antagonists & inhibitors; D004317:Doxorubicin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007247:Infertility, Female / Q000139:chemically induced / Q000517:prevention & control; D049590:Postpartum Period; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D011256:Pregnancy Outcome; D020011:Protective Agents / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects; D014886:Weaning
chemical_list: D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D002316:Cardiotonic Agents; D054715:Cardiotoxins; D020011:Protective Agents; C503872:caisequestrin 2, rat; D011929:Razoxane; D004317:Doxorubicin