title: Modifications in dynamic contrast-enhanced magnetic resonance imaging parameters after α-particle-emitting ²²⁷Th-trastuzumab therapy of HER2-expressing ovarian cancer xenografts.
abstract: OBJECTIVE
  The purpose of this study was to investigate the effect of α-particle-emitting (227)Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of (227)Th-trastuzumab.
  
  
  METHODS
  Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm(3) (mean ± SEM) were treated with a single injection of either (227)Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of (227)Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors.
  
  
  RESULTS
  Significant increases of kep, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and kel, the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of kep and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01).
  
  
  CONCLUSIONS
  Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after (227)Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts.
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway. Electronic address: Helen.Heyerdahl@rr-research.no.
authors.forename: Helen
authors.initials: H
authors.lastname: Heyerdahl
authors.forename: Kathrine
authors.initials: K
authors.lastname: Røe
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 / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000528:radiation effects*; D003287:Contrast Media / Q000493:pharmacokinetics*; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D010949:Plasma / Q000378:metabolism; D016499:Radioimmunotherapy / Q000379:methods*; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013910:Thorium / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003287:Contrast Media; D018719:Erb-b2 Receptor Tyrosine Kinases; D013910:Thorium; D000068878:Trastuzumab