title: Treatment of HER2-expressing breast cancer and ovarian cancer cells with alpha particle-emitting 227Th-trastuzumab.
abstract: OBJECTIVE
  To evaluate the cytotoxic effects of low-dose-rate alpha particle-emitting radioimmunoconjugate (227)Th-p-isothiocyanato-benzyl-DOTA-trastuzumab ((227)Th-trastuzumab [where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]) internalized by breast and ovarian cancer cell lines in order to assess the potential of (227)Th-trastuzumab as a therapeutic agent against metastatic cancers that overexpress the HER2 oncogene.
  
  
  METHODS
  Clonogenic survival and cell growth rates of breast cancer cells treated with (227)Th-trastuzumab were compared with rates of cells treated with nonbinding (227)Th-rituximab, cold trastuzumab, and X-radiation. Cell growth experiments were also performed with ovarian cancer cells. Cell-associated radioactivity was measured at several time points, and the mean radiation dose to cells was calculated.
  
  
  RESULTS
  SKBR-3 cells got 50% of the mean absorbed radiation dose from internalized activity and 50% from cell surface-bound activity, while BT-474 and SKOV-3 cells got 75% radiation dose from internalized activity and 25% from cell surface-bound activity. Incubation of breast cancer cells with 2.5 kBq/ml (227)Th-trastuzumab for 1 h at 4°C, followed by washing, resulted in mean absorbed radiation doses of 2 to 2.5 Gy. A dose-dependent inhibition of cell growth and an increase in apoptosis were induced in all cell lines.
  
  
  CONCLUSIONS
  Clinically relevant activity concentrations of (227)Th-trastuzumab induced a specific cytotoxic effect in three HER2-expressing cell lines. The cytotoxic effect of (227)Th-trastuzumab was higher than that of single-dose X-radiation (relative biological effectiveness = 1.2). These results warrant further studies of treatment of breast cancer and ovarian cancer with (227)Th-trastuzumab.
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: Helen
authors.initials: H
authors.lastname: Heyerdahl
authors.forename: Cecilie
authors.initials: C
authors.lastname: Krogh
authors.forename: Jørgen
authors.initials: J
authors.lastname: Borrebæk
authors.forename: Åsmund
authors.initials: Å
authors.lastname: Larsen
authors.forename: Jostein
authors.initials: J
authors.lastname: Dahle
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects*; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000378:metabolism; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011879:Radiotherapy Dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012062:Relative Biological Effectiveness; D000069283:Rituximab; D000068878:Trastuzumab; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018796:Immunoconjugates; D009363:Neoplasm Proteins; D009942:Organometallic Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000069283:Rituximab; D000068878:Trastuzumab; C544340:thorium-227-DOTA-rituximab; C555438:thorium-227-p-isothiocyanato-benzyl-DOTA-trastuzumab