title: Pamidronate Attenuates Oxidative Stress and Energetic Metabolism Changes but Worsens Functional Outcomes in Acute Doxorubicin-Induced Cardiotoxicity in Rats.
abstract: BACKGROUND
  Cardiotoxicity is the major side effect of doxorubicin. As mechanisms that are involved in cardiotoxicity are ambiguous, new methods for attenuating cardiotoxicity are needed. Recent studies have shown that bisphosphonates can decrease oxidative stress. Therefore, the objective of this study was to evaluate the effect of pamidronate on preventing acute doxorubicin-induced cardiotoxicity.
  
  
  METHODS
  Sixty-four male Wistar rats were allocated into four groups: the control group (C), the pamidronate group (P), the doxorubicin group (D) and the doxorubicin/pamidronate group (DP). The rats in the P and DP groups received pamidronate injections (3 mg/kg, IP). After 24 hours, the rats in the D and DP groups received doxorubicin injections (20 mg/kg, IP). Forty-eight hours after doxorubicin injection, the rats were killed. Echocardiography, isolated heart study and biochemical analysis were performed.
  
  
  RESULTS
  Doxorubicin-induced acute cardiotoxicity showed increased matrix metalloproteinases (MMP)-2 activation, oxidative damage and induced alterations in myocardial energetic metabolism. Pamidronate did not inhibit MMP-2 activation but attenuated oxidative stress and improved myocardial energetic metabolism. Regarding cardiac function, the DP group exhibited a decrease in the left ventricular ejection fraction in the echocardiography and a decrease in +dP/dt in the isolated heart study compared with other groups. The same DP group presented serum hypocalcaemia.
  
  
  CONCLUSIONS
  Despite its ability to reduce oxidative stress and improve energy metabolism in the heart, pamidronate worsened systolic function in rats treated with doxorubicin, and therefore we cannot recommend its use in conjunction with anthracycline chemotherapy.
authors.affiliation: Faculdade de Medicina de Botucatu, Universidade Estadual Paulista - UNESP, Botucatu/SP (Brazil).
authors.forename: Paula Bernardo de
authors.initials: PB
authors.lastname: Carvalho
authors.forename: Andréa de Freitas
authors.initials: AF
authors.lastname: Gonçalves
authors.forename: Patrícia Helena Correa
authors.initials: PH
authors.lastname: Alegre
authors.forename: Paula Schmidt
authors.initials: PS
authors.lastname: Azevedo
authors.forename: Meliza Goi
authors.initials: MG
authors.lastname: Roscani
authors.forename: Carolina Marabesi
authors.initials: CM
authors.lastname: Bergamasco
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Modesto
authors.forename: Ana Angélica
authors.initials: AA
authors.lastname: Fernandes
authors.forename: Marcos Ferreira
authors.initials: MF
authors.lastname: Minicucci
authors.forename: Sergio Alberto Rupp
authors.initials: SA
authors.lastname: Paiva
authors.forename: Leonardo
authors.initials: L
authors.lastname: Antonio
authors.forename: Mamede
authors.initials: M
authors.lastname: Zornoff
authors.forename: Bertha Furlan
authors.initials: BF
authors.lastname: Polegato
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000097:blood; D066126:Cardiotoxicity / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D003971:Diastole / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects*; D004327:Drinking Behavior / Q000187:drug effects; D004452:Echocardiography; D004734:Energy Metabolism / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D000077268:Pamidronate; D010477:Perfusion; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D004164:Diphosphonates; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D000077268:Pamidronate; D002118:Calcium