title: Long-Term Toxicity of 213Bi-Labelled BSA in Mice.
abstract: BACKGROUND
  Short-term toxicological evaluations of alpha-radioimmunotherapy have been reported in preclinical assays, particularly using bismuth-213 (213Bi). Toxicity is greatly influenced not only by the pharmacokinetics and binding specificity of the vector but also by non-specific irradiation due to the circulating radiopharmaceutical in the blood. To assess this, an acute and chronic toxicity study was carried out in mice injected with 213Bi-labelled Bovine Serum Albumin (213Bi-BSA) as an example of a long-term circulating vector.
  
  
  METHODS
  Biodistribution of 213Bi-BSA and 125I-BSA were compared in order to evaluate 213Bi uptake by healthy organs. The doses to organs for injected 213Bi-BSA were calculated. Groups of nude mice were injected with 3.7, 7.4 and 11.1 MBq of 213Bi-BSA and monitored for 385 days. Plasma parameters, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine, were measured and blood cell counts (white blood cells, platelets and red blood cells) were performed. Mouse organs were examined histologically at different time points.
  
  
  RESULTS
  Haematological toxicity was transient and non-limiting for all evaluated injected activities. At the highest injected activity (11.1 MBq), mice died from liver and kidney failure (median survival of 189 days). This liver toxicity was identified by an increase in both ALT and AST and by histological examination. Mice injected with 7.4 MBq of 213Bi-BSA (median survival of 324 days) had an increase in plasma BUN and creatinine due to impaired kidney function, confirmed by histological examination. Injection of 3.7 MBq of 213Bi-BSA was safe, with no plasma enzyme modifications or histological abnormalities.
  
  
  CONCLUSIONS
  Haematological toxicity was not limiting in this study. Liver failure was observed at the highest injected activity (11.1 MBq), consistent with liver damage observed in human clinical trials. Intermediate injected activity (7.4 MBq) should be used with caution because of the risk of long-term toxicity to kidneys.
authors.affiliation: Nuclear Oncology, Nantes-Angers Cancer Research Center (CRCNA) UMR 892 Inserm, Nantes, France.|University of Nantes, Nantes, France.|CNRS, UMR 6299, Nantes, France.|L'UNAM University, Oniris, AMaROC Unit, Nantes, France.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Dorso
authors.affiliation: Nuclear Oncology, Nantes-Angers Cancer Research Center (CRCNA) UMR 892 Inserm, Nantes, France.|University of Nantes, Nantes, France.|CNRS, UMR 6299, Nantes, France.|Biochemistry Department, Laënnec Hospital, Nantes, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Bigot-Corbel
authors.affiliation: L'UNAM University, Oniris, AMaROC Unit, Nantes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Abadie
authors.affiliation: Nuclear Oncology, Nantes-Angers Cancer Research Center (CRCNA) UMR 892 Inserm, Nantes, France.|University of Nantes, Nantes, France.|CNRS, UMR 6299, Nantes, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Diab
authors.affiliation: Nuclear Oncology, Nantes-Angers Cancer Research Center (CRCNA) UMR 892 Inserm, Nantes, France.|University of Nantes, Nantes, France.|CNRS, UMR 6299, Nantes, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gouard
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: Nuclear Oncology, Nantes-Angers Cancer Research Center (CRCNA) UMR 892 Inserm, Nantes, France.|University of Nantes, Nantes, France.|CNRS, UMR 6299, Nantes, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Maurel
authors.affiliation: Nuclear Oncology, Nantes-Angers Cancer Research Center (CRCNA) UMR 892 Inserm, Nantes, France.|University of Nantes, Nantes, France.|CNRS, UMR 6299, Nantes, France.|Nuclear Medicine, ICO institut de Cancerologie de l'Ouest - Centre René Gauducheau, Nantes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Chérel
authors.affiliation: Nuclear Oncology, Nantes-Angers Cancer Research Center (CRCNA) UMR 892 Inserm, Nantes, France.|University of Nantes, Nantes, France.|CNRS, UMR 6299, Nantes, France.|Nuclear Medicine, University Hospital, Nantes, France.
authors.forename: François
authors.initials: F
authors.lastname: Davodeau
mesh_terms: D000818:Animals; D001729:Bismuth / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D002417:Cattle; D005260:Female; D051379:Mice; D008819:Mice, Nude; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D014018:Tissue Distribution
chemical_list: D012710:Serum Albumin, Bovine; D001729:Bismuth