title: Control of prostate cancer spheroid growth using 213Bi-labeled multiple targeted alpha radioimmunoconjugates.
abstract: BACKGROUND
  Micrometastasis is a major problem for prostate cancer (CaP) patients. Our study investigated the therapeutic potential of multiple targeted alpha-therapy (MTAT) in the treatment of CaP micrometastases (spheroids) using (213)Bi-labeled multiple targeted alpha-radioimmunoconjugates.
  
  
  METHODS
  The expression of multiple tumor-associated antigens (TAAs) on frozen sections of human fresh CaP tissues and spheroids cultured from DU 145 and LNCaP-LN3 CaP cell lines was detected by immunohistochemistry and flow cytometry. Targeting vectors were two monoclonal antibodies (MAbs), and plasminogen activator inhibitor type 2 (PAI2) that binds to cell surface urokinase plasminogen activator (uPA). These vectors were labeled with (213)Bi using standard methodology. DU 145 and LNCaP-LN3 spheroids were incubated with different activities of test and control alpha-conjugates (ACs), and spheroid growth was measured for volume change and growth delay over a 50-day period using light microscopy.
  
  
  RESULTS
  TAAs were expressed heterogeneously on frozen sections from human CaP tissues and CaP spheroids. MTAT combining three ACs (one-third dose of each) with an activity of 6.4 MBq/ml completely targeted small DU 145 and LNCaP-LN3 spheroids (diameter <100 microm) and slightly regressed the growth of medium spheroids (180-200 microm); MTAT with 2.2 or 4.8 MBq/ml activities delayed the growth of tumor spheroids.
  
  
  CONCLUSIONS
  Our results suggest that the cytotoxicity of MTAT to CaP spheroids is highly dependent on antigenic expression, concentration of radioactivity and spheroid size. MTAT may be a potent therapeutic agent for micrometastases, effectively targeting small CaP cell clusters, and overcoming the heterogeneous expression of targeted antigens.
authors.affiliation: Centre for Experimental Radiation Oncology, Cancer Care Centre, St. George Hospital, New South Wales, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Syed M
authors.initials: SM
authors.lastname: Abbas Rizvi
authors.forename: Michele C
authors.initials: MC
authors.lastname: Madigan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cozzi
authors.forename: Carl A
authors.initials: CA
authors.lastname: Power
authors.forename: Chang F
authors.initials: CF
authors.lastname: Qu
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Christos
authors.initials: C
authors.lastname: Apostolidis
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Allen
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D001729:Bismuth / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology; D007150:Immunohistochemistry; D008297:Male; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D018874:Spheroids, Cellular
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D018796:Immunoconjugates; D001729:Bismuth