Inhibition of micrometastatic prostate cancer cell spread in animal models by 213Bilabeled multiple targeted alpha radioimmunoconjugates.
OBJECTIVE
To investigate the therapeutic potential of 213Bilabeled multiple targeted alpha-radioimmunoconjugates for treating prostate cancer (CaP) micrometastases in mouse models.


METHODS
PC-3 CaP cells were implanted s.c., in the prostate, and intratibially in NODSCID mice. The expression of multiple tumor-associated antigens on tumor xenografts and micrometastases was detected by immunohistochemistry. Targeting vectors were two monoclonal antibodies, and a plasminogen activator inhibitor type 2 that binds to cell surface urokinase plasminogen activator, labeled with 213Bi using standard methodology. In vivo efficacy of multiple alpha conjugates (MTAT) at different activities was evaluated in these mouse models. Tumor growth was monitored during observations and local regional lymph node metastases were assessed at the end of experiments.


RESULTS
The take rate of PC-3 cells was 100% for each route of injection. The tumor-associated antigens (MUC1, urokinase plasminogen activator, and BLCA-38) were heterogeneously expressed on primary tumors and metastatic cancer clusters at transit. A single i.p. injection of MTAT (test) at high and low doses caused regression of the growth of primary tumors and prevented local lymph node metastases in a concentration-dependent fashion; it also caused cancer cells to undergo necrosis and apoptosis.


CONCLUSIONS
Our results suggest that MTAT can impede primary PC-3 CaP growth at three different sites in vivo through induction of apoptosis, and can prevent the spread of cancer cells and target lymph node micrometastases in a concentration-dependent manner. MTAT, by targeting multiple antigens, can overcome heterogeneous antigen expression to kill small CaP cell clusters, thus providing a potent therapy for micrometastases.
Li
Yong
Y
Cancer Care Centre, St George Hospital, New South Wales, Australia. y.li@unsw.edu.au
Song
Emma
E
Abbas Rizvi
Syed M
SM
Power
Carl A
CA
Beretov
Julia
J
Raja
Chand
C
Cozzi
Paul J
PJ
Morgenstern
Alfred
A
Apostolidis
Christos
C
Allen
Barry J
BJ
Russell
Pamela J
PJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001729:Bismuth; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D011868:Radioisotopes / Q000627:therapeutic use; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; C493191:BLCA-38 monoclonal antibody; D018796:Immunoconjugates; C434325:MUC-1 monoclonal antibody; D011868:Radioisotopes; D014568:Urokinase-Type Plasminogen Activator; D001729:Bismuth