title: Fractionated therapy of HER2-expressing breast and ovarian cancer xenografts in mice with targeted alpha emitting 227Th-DOTA-p-benzyl-trastuzumab.
abstract: BACKGROUND
  The aim of this study was to investigate therapeutic efficacy and normal tissue toxicity of single dosage and fractionated targeted alpha therapy (TAT) in mice with HER2-expressing breast and ovarian cancer xenografts using the low dose rate radioimmunoconjugate (227)Th-DOTA-p-benzyl-trastuzumab.
  
  
  RESULTS
  Nude mice carrying HER2-overexpressing subcutaneous SKOV-3 or SKBR-3 xenografts were treated with 1000 kBq/kg (227)Th-trastuzumab as single injection or four injections of 250 kBq/kg with intervals of 4-5 days, 2 weeks, or 4 weeks. Control animals were treated with normal saline or unlabeled trastuzumab. In SKOV-3 xenografts tumor growth to 10-fold size was delayed (p<0.01) and survival with tumor diameter less than 16 mm was prolonged (p<0.05) in all TAT groups compared to the control groups. No statistically significant differences were seen among the treated groups. In SKBR-3 xenografts tumor growth to 10-fold size was delayed in the single injection and 4-5 days interval groups (p<0.001) and all except the 4 weeks interval TAT group showed improved survival to the control groups (p<0.05). Toxicity was assessed by blood cell counts, clinical chemistry measurements and body weight. Transient reduction in white blood cells was seen for the single injection and 4-5 days interval groups (p<0.05). No significant changes were seen in red blood cells, platelets or clinical chemistry parameters. Survival without life threatening loss of body weight was significantly prolonged in 4 weeks interval group compared to single injection group (p<0.05) for SKOV-3 animals and in 2 weeks interval group compared with the 4-5 days interval groups (p<0.05) for SKBR-3 animals.
  
  
  CONCLUSIONS
  The same concentration of radioactivity split into several fractions may improve toxicity of (227)Th-radioimmunotherapy while the therapeutic effect is maintained. Thus, it might be possible to increase the cumulative absorbed radiation dose to tumor with acceptable toxicity by fractionation of the dosage.
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Oslo University, Hospital - The Norwegian Radium Hospital, Oslo, Norway. Helen.Heyerdahl@rr-research.no
authors.forename: Helen
authors.initials: H
authors.lastname: Heyerdahl
authors.forename: Nasir
authors.initials: N
authors.lastname: Abbas
authors.forename: Ellen Mengshoel
authors.initials: EM
authors.lastname: Brevik
authors.forename: Camilla
authors.initials: C
authors.lastname: Mollatt
authors.forename: Jostein
authors.initials: J
authors.lastname: Dahle
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001345:Autoradiography; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007958:Leukocyte Count; D051379:Mice; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016019:Survival Analysis; D013997:Time Factors; D000068878:Trastuzumab; D047368:Tumor Burden; D015431:Weight Loss; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D006573:Heterocyclic Compounds, 1-Ring; D009942:Organometallic Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C577212:thorium-227DOTA-p-benzyl-trastuzumab; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid