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.
Center for Experimental Radiation Oncology, Cancer Care Center, St. George Hospital, Gray Street, Kogarah, NSW 2217, Australia.
Yong
Y
Li
Syed M
SM
Abbas Rizvi
Julie M
JM
Blair nee Brown
Paul J
PJ
Cozzi
Chang F
CF
Qu
Kim T
KT
Ow
Patrick N
PN
Tam
Alan C
AC
Perkins
Pamela J
PJ
Russell
Barry J
BJ
Allen
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