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Research Articles

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

Departments of ¹ Nuclear Medicine and ² Radiooncology, Technische Universitaet Muenchen; ³ Bundeswehr Institute of Radiobiology, German Armed Forces, Munich, Germany; ⁴ Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany; and ⁵ European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany

Requests for reprints: Christof Seidl, Department of Nuclear Medicine, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany. Phone: 49-89-4140-4558; Fax: 49-89-4140-4897. E-mail: Christof.Seidl{at}lrz.tum.de

Abstract

Tumor cells are efficiently killed after incubation with -emitter immunoconjugates targeting tumor-specific antigens. Therefore, application of -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 -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 -emitters in tumor cells could help to improve strategies of -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, ²¹³Bi-triggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen. [Mol Cancer Ther 2007;6(8):2346–59]

Grant support: Germany Ministry of Defence (M. Abend) and Deutsche Forschungsgemeinschaft grants SE 962/2-4 (R. Senekowitsch-Schmidtke).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ U. Roessler, personal communication.

Received 2/26/07; revised 5/ 8/07; accepted 6/29/07.