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 catastrophe

Abstract

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 213 Bi 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 213 Bi-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 213 Bi-induced cell death was initiated by G 2 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 213 Bi activates death cascades different from apoptosis. Furthermore, 213 Bitriggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen. [Mol Cancer Ther 2007;6(8):2346 -59]

Therapeutic efficacy and toxicity of 225Ac-labelled vs. 213Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis

“…In contrast, the proportion of apoptotic cells was lower than 1%. This result is in line with previous findings according to which 213 Bi-anti-d9-E-cadherin immunoconjugates induced necrosis but not apoptosis in the gastric cancer cell line HSC45-M2 [40,41]. Predominant induction of necrosis compared to apoptosis by 225 Ac-DOTA-F3 and 213 Bi-DTPA-F3 might have been because of the high activities administered.…”

A Radiation-Induced Gene Signature Distinguishes Post-Chernobyl from Sporadic Papillary Thyroid Cancers

“…Most of the genes (82%) were detected similarly with both methods. The overlap of similar gene expression detected with both methods is in line with experience in our laboratory using the same techniques on HSC cells exposed to a radioisotope, with an overlap of 90.3% (20).…”

Death through a tragedy: mitotic catastrophe

“…This may also be true for heterogeneous and genetically instable clinical tumor samples exposed to radiation. [54][55][56] Most experimental facts concerning the biology of MC are based on observations obtained using cells growing in monolayer, and even if these may serve well as models, extrapolation to three-dimensional in vivo structures should be done with great consideration. 57 In fact, specific cell-cell and cell-matrix interactions may be as important as the genomic background for the MC response, although this point of view is frequently neglected.…”