title: Comparing high LET 227Th- and low LET 177Lu-trastuzumab in mice with HER-2 positive SKBR-3 xenografts.
abstract: The aim of the present study was to compare the biodistribution, normal tissue toxicity and therapeutic effect of the alpha-particle emitting 227Th-trastuzumab and the beta-particle emitting 177Lu-trastuzumab in mice with HER2- expressing SKBR-3 breast cancer xenografts.
  
  
  METHODS
  Biodistributions of the two radioimmunoconjugates were determined at different time points after i.v. injection. Inhibition of tumor growth was measured after single injection of 227Th-trastuzumab (200, 400, 600 or 1000 kBq/kg), 177Lu-trastuzumab (40 or 200 MBq/kg) or saline. The toxicity profiles were compared by measurements of body weight,clinical chemistry and hematological parameters, as well as histological examination of tissue specimens.
  
  
  RESULTS
  400 kBq/kg of 227Th-trastuzumab and 40 MBq/kg of 177Lu-trastuzumab both resulted in an absorbed radiation dose to tumor of approximately 3 Gy. A significant anti-tumor effect and increased survival were observed at injected dosages of 400-1000 kBq/kg of 227Th-trastuzumab and 200 MBq/kg of 177Lu-trastuzumab as compared to the saline control. When compared at the same therapeutic effect level (100% prolonged growth delay as compared to control) the absorbed radiation dose of 227Th-trastuzumab was 3 times lower than with 177Lu-trastuzumab, indicating a relative biological effect (RBE) of 2.8 for 227Th-trastuzumab. In contrast, when compared at the same temporary decrease of WBC count (50% decrease in number of white blood cells as compared to control), the growth delay was 3 times longer with 177Lutrastuzumab than with 227Th-trastuzumab, which indicates that the therapeutic index was three times higher for 177Lutrastuzumab than for 227Th-trastuzumab.
  
  
  CONCLUSIONS
  In this xenograft model the RBE was higher for 227Th-trastuzumab than for 177Lu-trastuzumab, while the therapeutic index of 177Lu-trastuzumab was superior to that of 227Th-trastuzumab.
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway. nasir.abbas@rr-research.no
authors.forename: Nasir
authors.initials: N
authors.lastname: Abbas
authors.forename: Helen
authors.initials: H
authors.lastname: Heyerdahl
authors.forename: Øyvind S
authors.initials: ØS
authors.lastname: Bruland
authors.forename: Ellen Mengshoel
authors.initials: EM
authors.lastname: Brevik
authors.forename: Jostein
authors.initials: J
authors.lastname: Dahle
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001610:Beta Particles / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007958:Leukocyte Count; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases; D014018:Tissue Distribution; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C577212:thorium-227DOTA-p-benzyl-trastuzumab; C508053:ERBB2 protein, human