title: Cytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate.
abstract: HER-2 has been implicated in the oncogenesis of human prostate cancer (CaP) and is the target of a new treatment for metastatic breast cancer using the humanised monoclonal antibody (MAb) trastuzumab (Herceptin). In this study, a novel alpha-particle emitting [213Bi]Herceptin construct, which targets the HER-2 extracellular domain on CaP cells, was prepared and evaluated in vitro. We used immunocytochemistry, flow cytometry and Western blot analysis to examine the expression of HER-2 in a panel of established human CaP cell lines, used the MTS assay to evaluate the cytotoxicity of 213Bi-Herceptin on these cell lines and the TUNEL assay to document apoptosis. The results indicate that LNCaP-LN3 cells express high levels of HER-2 protein, in contrast, DU 145 cells express low to medium levels, and PC-3 cells express an undetectable level of HER-2 protein. 213Bi-Herceptin was specifically cytotoxic to LNCaP-LN3 cells in a concentration-dependent fashion, cause the cells to undergo apoptosis, whereas DU 145 showed an HER-2 level-dependent response to 213Bi-Herceptin cytotoxicity. In contrast, PC-3 cells were resistant to 213Bi-Herceptin-induced cytotoxicity. The 213Bi-Herceptin induced apoptosis in LNCaP-LN3 cells could be inhibited by incubation with unlabeled Herceptin. Our results suggest that 213Bi-Herceptin alpha-conjugate might be a promising new agent for the treatment of preangiogenic cancer cell clusters or micro-metastases with high levels of HER-2 expression.
authors.affiliation: Center for Experimental Radiation Oncology, Cancer Care Center, St George Hospital, Gray St, Kogarah 2217, New South Wales, Australia.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cozzi
authors.forename: Chang F
authors.initials: CF
authors.lastname: Qu
authors.forename: David Y
authors.initials: DY
authors.lastname: Zhang
authors.forename: Syed M
authors.initials: SM
authors.lastname: Abbas Rizvi
authors.forename: Chand
authors.initials: C
authors.lastname: Raja
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Allen
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000528:radiation effects*; D001729:Bismuth / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001729:Bismuth; D011868:Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab