In vivo and in vitro inhibition of pancreatic cancer growth by targeted alpha therapy using 213Bi-CHX.A"-C595.
OBJECTIVE
The aim of this study was to investigate the effect of targeted alpha therapy for the control of in vitro pancreatic cancer cell clusters and micrometastatic cancer lesions in vivo.


METHODS
The expression of tumor-associated antigen MUC-1 on three pancreatic cancer cell clusters and animal xenografts was detected by indirect immmunostaining. Monoclonal antibodies C595 (test) and A2 (non-specific control) were labeled with 213Bi using the chelator CHX.A" to form the alpha-immunoconjugate (AIC). Cell clusters were incubated with AIC and examined at 48 h. Apoptosis was documented using the TUNEL assay. In vivo, an antiproliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AIC by regional or systemic administration. Changes in tumor progression were assessed by tumor size.


RESULTS
MUC-1 is strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The AICs can target and kill cancer cell clusters (100 mm) in vitro. Some 73-81 % of cells were TUNEL positive cells in the clusters after incubation with AIC. At two days post- cell inoculation in mice, a single local injection of 74 and 148 MBq/kg of AIC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of AIC cause significant tumor growth delay after 16 weeks, compared with the nonspecific control providing 333 MBq/kg after 16 weeks.


CONCLUSIONS
CFPAC-1, PANC-1 and CAPAN-1 pancreatic cancer cell clusters and pancreatic tumor xenografts show high expression of the MUC-1 target antigen. 213Bi-C595 can specifically target and regress pancreatic cancer cell clusters in vitro, and delay and inhibit tumor growth in vivo. 213Bi-C595 may be a useful agent for the treatment of micrometastatic pancreatic cancer with overexpression of MUC 1 antigen in post-surgical patients with minimal residual disease.
Qu
Chang F
CF
Centre for Experimental Radiation Oncology, Cancer Care Centre, St George Hospital, New South Wales, Australia.
Songl
Yan J
YJ
Rizvi
Syed M A
SM
Li
Yong
Y
Smith
Ross
R
Perkins
Alan C
AC
Morgenstern
Alfred
A
Brechbiel
Martin
M
Allen
Barry J
BJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm; D001729:Bismuth / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D017879:Isothiocyanates / Q000627:therapeutic use*; D051379:Mice; D018396:Mucin-1; D009077:Mucins / Q000032:analysis / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000532:radiotherapy*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016499:Radioimmunotherapy; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D017879:Isothiocyanates; C060192:MUC1 protein, human; D018396:Mucin-1; D009077:Mucins; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid; D001729:Bismuth