213bi-Induced Death of Hsc45-M2 Gastric Cancer Cells Is Characterized by G2 Arrest and Up-Regulation of Genes Known to Prevent Apoptosis but Induce Necrosis and Mitotic Catastrpophe

Tumor cells are efficiently killed after incubation with A-emitter immunoconjugates targeting tumor-specific antigens. Therefore, application of A-emitter immunoconjugates is a promising therapeutic option for treatment of carcinomas that are characterized by dissemination of single tumor cells in the peritoneum like ovarian cancer or gastric cancer. In diffuse-type gastric cancer, 10% of patients express mutant d9-E-cadherin on the surface of tumor cells that is targeted by the monoclonal antibody d9MAb. Coupling of the A-emitter 213Bi to d9MAb provides an efficient tool to eliminate HSC45-M2 gastric cancer cells expressing d9-E-cadherin in vitro and in vivo. Elucidation of the molecular mechanisms triggered by A-emitters in tumor cells could help to improve strategies of A-emitter radioimmunotherapy. For that purpose, gene expression of 213Bi-treated tumor cells was quantified using a real time quantitative-PCR low-density array covering 380 genes in combination with analysis of cell proliferation and the mode of cell death. We could show that 213Bi-induced cell death was initiated by G2 arrest;up-regulation of tumor necrosis factor (TNF), SPHK1, STAT5A, p21, MYT1, and SSTR3; and down-regulation of SPP1, CDC25 phosphatases, and of genes involved in chromosome segregation. Together with morphologic changes, these results suggest that 213Bi activates death cascades different from apoptosis. Furthermore, 213Bitriggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen.

SEIDL C.;  PORT M.;  GILBERTZ K.;  MORGENSTERN Alfred;  BRUCHERTSEIFER Frank;  SCHWAIGER M.;  ROEPER B.;  SENEKOWITSCH-SCHMIDTKE R.;  ABEND M.; 

2007-08-24

AMER ASSOC CANCER RESEARCH

JRC38225

https://publications.jrc.ec.europa.eu/repository/handle/JRC38225,   

10.1158/1535-7163.MCT-07-0132,