Inhibition ofMicrometastatic Prostate Cancer Cell Spread in Animal Models By 213BilabeledMultipleTargeted Alpha-Radioimmunoconjugates

Purpose: To investigate the therapeutic potential of 213Bilabeled multiple targeted a-radioimmunoconjugates for treatingprostate cancer (CaP)micrometastases inmousemodels. Experimental Design: 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 andmicrometastaseswas detected by immunohistochemistry.Targeting vectorswere twomonoclonal antibodies, and a plasminogen activator inhibitor type 2 that binds to cell surface urokinase plasminogen activator, labeledwith 213Bi using standardmethodology. In vivo efficacy ofmultiple a 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 was100% 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 nodemetastases in a concentration-dependent fashion; it also caused cancer cells to undergo necrosis and apoptosis. Conclusions: Our results suggest thatMTATcan 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 Y.;  SONG E.;  ABBAS RIZVI S. M.;  POWER C. A.;  BERETOV J.;  RAJA C.;  COZZI P. J.;  MORGENSTERN Alfred;  APOSTOLIDIS Christos;  ALLEN B. J.;  RUSSELL P. J.; 

2009-02-19

AMER ASSOC CANCER RESEARCH

JRC50507

1078-0432,   

www.aacrjournals.org,    https://publications.jrc.ec.europa.eu/repository/handle/JRC50507,   

10.1158/1078-0432.CCR-08-1203,