title: Which sequence best protects the heart against trastuzumab and anthracycline toxicity? An electron microscopy study in rats.
abstract: OBJECTIVE
  Two effective cytotoxic agents, doxorubicin and trastuzumab, are associated with potentially life-threatening cardiotoxicity. The present study was designed to investigate cardiotoxicity aggravated by the timing of administration of trastuzumab and doxorubicin in rats.
  
  
  METHODS
  Twenty-four rats were randomly assigned to one of four groups. These received one of the following treatment drug regimens administered via intraperitoneal injection: (i) 0.9% saline control (n=6); (ii) doxorubicin (5 mg/kg) on day 1 then trastuzumab 10 mg/kg on day 15 (n=6); (iii) trastuzumab 10 mg/ kg on day 1 then doxorubicin (5 mg/kg) on day 15 (n=6) or (iv) doxorubicin (5 mg/kg) on day 1 and trastuzumab 10 mg/ kg on day 1 (n=6). On the 30th day, the hearts were processed for pathological analysis by electron microscopy.
  
  
  RESULTS
  Electron microscopy revealed an ultrastructurally normal heart tissue in the control group. At electron microscopic examination of the tissue samples in the second and fourth group, a mild degree of dilation was observed in the peri-nuclear cisternae of some heart muscle cells. In the third group, pathological changes were detected in mitochondria. These exhibited prominent cristae, which also showed a mild degree of ultrastructural pathology in mitochondria.
  
  
  CONCLUSIONS
  Based on electron microscopy findings, sequential administration of anthracycline first, followed by trastuzumab is safer in terms of cardiotoxicity, while the most toxic schedule for the rat heart was trastuzumab first, followed by anthracycline.
authors: Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Neyran
authors: N
authors: Kertmen
authors: Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Sercan
authors: S
authors: Aksoy
authors: Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors: Aysegul
authors: A
authors: Uner
authors: Department of Anatomy, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors: Mustafa
authors: M
authors: Sargon
authors: Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors: Ozgur
authors: O
authors: Ozkayar
authors: Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Ozge
authors: O
authors: Keskin
authors: Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Taner
authors: T
authors: Babacan
authors: Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Furkan
authors: F
authors: Sarici
authors: Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey.
authors: Mehmet A N
authors: MA
authors: Sendur
authors: Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Zafer
authors: Z
authors: Arik
authors: Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
authors: Serkan
authors: S
authors: Akin
authors: Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey altundag66@yahoo.com.
authors: Kadri
authors: K
authors: Altundag
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004317:Doxorubicin; D000068878:Trastuzumab
keywords: Trastuzumab; anthracyline; cardiotoxicity; sequence