In vivo and in vitro inhibition of pancreatic cancer growth by targeted alpha therapy using 213Bi-CHX.A”-C595

Abstract

Purpose: 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 213 Bi 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. 213 Bi-C595 can specifically target and regress pancreatic cancer cell clusters in vitro, and delay and inhibit tumor growth in vivo. 213 Bi-C595 may be a useful agent for the treatment of micrometastatic pancreatic cancer with overexpression of MUC1 antigen in post-surgical patients with minimal residual disease.

Nontoxic radioactive Listeria at is a highly effective therapy against metastatic pancreatic cancer

“…Although a strong accumulation of Listeria at was found in the primary tumors on day 1, no multiplication of Listeria at was observed between days 1 and 3 or between days 3 and 7. Therefore, we also analyzed earlier time intervals (3,6, and 72 h after injection of the bacteria) and found that Listeria at did multiply to some degree between 3 and 6 h, but the number of cfu of Listeria at decreased between 6 and 72 h in the primary tumor (Fig. 1B).…”

“…Listeria at multiplied strongly in the metastases between days 1 and 3, but not in the primary tumors, and the cfu of Listeria at decreased in both metastases and tumor between days 3 and 7. We also analyzed the biodistribution and clearance at earlier time points (3,6, and 72 h) and showed that the Listeria at strongly multiplied in the metastases at all time points, but only to some degree in the primary tumors between 3 and 6 h (Table S1). A similar pattern of biodistribution of the Listeria at cfu was observed with Listeria at Ab (Table S2).…”

“…There have been attempts to use targeted radionuclide therapy in form of radiolabeled tumor-specific Abs (radioimmunotherapy) for treatment of pancreatic cancer. However, radioimmunotherapy of pancreatic cancer has shown very modest results both preclinically (6)(7)(8) and in cancer patients with unresectable liver metastases (9). Obviously, new choices of targeting vehicles are needed to make targeted radionuclide therapy successful in the treatment of pancreatic cancer.…”

Biological Chemistry of Antimony and Bismuth

“…Bismuth subsalicylate (BSS, Pepto-Bismol) has been used for the fast relief of heartburn, nausea, indigestion, upset stomach, and diarrhea. Its structure and hydrolysis mechanism have been modeled on two bismuth oxosalicylate clusters, that is, [Bi 38 O 44 (Hsal) 26 (Me 2 CO) 16 16 (H 2 O) 2 ], following the transposition of predominance when extend the crystal growth time, revealing a possible hydrolysis process for BSS [14]. Another type of bismuth drug is based on bismuth citrate complexes such as colloidal bismuth subcitrate (CBS, De-Nol; Gist Brocades and Yamanouchi), and ranitidine bismuth citrate (RBC, Tritec and Pylorid, GSK), which is used worldwide to treat various gastrointestinal diseases, caused by the H. pylori infection [15][16][17][18].…”

“…The 213 Bi labeled monoclonal antibody C595 can target the MUC1 protein that is overexpressed in $90% of tested tumor samples and effectively inhibit growth of pancreatic cell clusters and preangiogenic lesions in vivo, eventually killing cancer micrometastases. This suggests that 213 Bi treatment may have a role as adjuvant therapy immediately after resection of macroscopic tumor to prevent recurrence [26]. Bismuth compounds not only inhibit cancer cells directly but also reduce the side effects of platinum-based anticancer drugs such as cisplatin and its analogues.…”