Inhibition of micrometastatic prostate cancer cell spread in animal models by 213Bilabeled multiple targeted alpha radioimmunoconjugates.

Abstract

PURPOSE:

To investigate the therapeutic potential of 213Bilabeled multiple targeted alpha-radioimmunoconjugates for treating prostate cancer (CaP) micrometastases in mouse models.

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 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.

• Authors: Yong Li, Emma Song, Syed M Abbas Rizvi, Carl A Power, Julia Beretov, Chand Raja, Paul J Cozzi, Alfred Morgenstern, Christos Apostolidis, Barry J Allen, Pamela J Russell
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 3 Pg. 865-75 (Feb 01 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19188157 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• BLCA-38 monoclonal antibody
• Immunoconjugates
• MUC-1 monoclonal antibody
• Radioisotopes
• Urokinase-Type Plasminogen Activator
• Bismuth

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Bismuth
• Cell Line, Tumor
• Disease Models, Animal
• Humans
• Immunoconjugates (therapeutic use)
• Male
• Mice
• Mice, Nude
• Mice, SCID
• Neoplasm Metastasis (prevention & control)
• Neoplasm Transplantation
• Prostatic Neoplasms (pathology, therapy)
• Radioisotopes (therapeutic use)
• Urokinase-Type Plasminogen Activator (antagonists & inhibitors)