Antigenic expression of human metastatic prostate cancer cell lines for in vitro multiple-targeted alpha-therapy with 213Bi-conjugates.
OBJECTIVE
Control of metastatic prostate cancer (CaP) is an elusive objective. Some 30% of patients with clinically localized CaP will develop micrometastatic disease. Defining the expression of tumor-associated antigens on CaP will enable appropriate selection of therapeutic targets.


METHODS
The expression of tumor-associated antigens on CaP cell lines (PC-3, DU 145, and LNCaP-LN3) was detected by immunohistochemistry and flow cytometry. Test and control alpha-conjugates were prepared using monoclonal antibodies, an inhibitor, plasminogen activator inhibitor type 2, that binds to the cell-membrane-bound protease, urokinase plasminogen activator, and a control protein labeled with (213)Bi using standard methods. These were used singly or together against three different CaP cell lines in vitro. The cytotoxicity of the alpha-conjugates was assessed using the [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] (MTS) assay.


RESULTS
The PC-3 and DU 145 cancer cell lines expressed antigens that bind monoclonal antibodies BLCA-38 and #394 (mouse anti-human urokinase plasminogen activator B-chain) but not J591. The LNCaP-LN3 cells bound J591 but not #394 or BLCA-38. For the PC-3, DU 145, and LNCaP-LN3 cell lines, multiple-targeted alpha-therapy combining four alpha-conjugates (one-quarter doses of each) gave D(0) (37% cell survival) values of 15, 17, and 27 microCi/mL compared with those of the controls of 272, 289, and 281 microCi/mL, respectively.


CONCLUSIONS
Metastatic prostate cancer-associated antigens recognized by multiple monoclonal antibodies are potential targets for alpha-therapy. Multiple-targeted alpha-therapy produced cytotoxicity specific to three CaP cell lines and may form the basis of treatment for micrometastatic CaP, overcoming the heterogeneity of expression of the targeted antigens.
Li
Yong
Y
Center for Experimental Radiation Oncology, Cancer Care Center, St. George Hospital, Gray Street, Kogarah, NSW 2217, Australia.
Abbas Rizvi
Syed M
SM
Blair nee Brown
Julie M
JM
Cozzi
Paul J
PJ
Qu
Chang F
CF
Ow
Kim T
KT
Tam
Patrick N
PN
Perkins
Alan C
AC
Russell
Pamela J
PJ
Allen
Barry J
BJ
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000032:analysis*; D017209:Apoptosis; D001729:Bismuth / Q000627:therapeutic use*; D045744:Cell Line, Tumor / Q000276:immunology; D049109:Cell Proliferation / Q000528:radiation effects; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D008297:Male; D017396:Plasminogen Activator Inhibitor 2 / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D018796:Immunoconjugates; D017396:Plasminogen Activator Inhibitor 2; D011868:Radioisotopes; D001729:Bismuth