title: Cytotoxicity of breast cancer cells overexpressing HER2/neu by 213Bi-Herceptin radioimmunoconjugate.
abstract: HER2 is the target of a new treatment for metastatic breast cancer using the humanized monoclonal antibody (MAb) trastuzumb (Herceptin). A novel alpha-particle emitting (213)Bi-Herceptin construct, targeting the HER2 extracellular domain on breast cancer cells, was produced by chelation and characterized in vitro in this study. We used Western blot and flow cytometry analysis to examine the expression of HER2 in a panel of established human metastatic breast cancer cell lines (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) MTS assay to evaluate the cytotoxicity and the TUNEL assay to analyze cellular apoptosis. Our results demonstrate that the human breast cancer cell lines BT-474 and SK-BR-3 express high levels of HER2 protein while MDA-231 expresses low levels of HER2. (213)Bi-Herceptin alpha conjugate (AC) was specifically cytotoxic to these cell lines in a HER2 level-dependent fashion, resulting in the cellular death through apoptosis. These results suggest that (231)Bi-Herceptin AC could be a novel agent for the treatment of breast cancer cell clusters or micro-metastases with high levels of HER2 expression.
authors.affiliation: Centre for Experimental Radiation Oncology, Cancer Care Centre, St George Hospital, Kogarah, NSW 2217, Australia.
authors.forename: David Y
authors.initials: DY
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Syed M Abbas
authors.initials: SM
authors.lastname: Rizvi
authors.forename: Changfa
authors.initials: C
authors.lastname: Qu
authors.forename: John
authors.initials: J
authors.lastname: Kearsley
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Allen
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000528:radiation effects; D001729:Bismuth / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D016499:Radioimmunotherapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001729:Bismuth; D018796:Immunoconjugates; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human