Title: Cell Death Triggered by Alpha-emitting 213Bi-immunoconjugates in HSC45-M2 Gastric Cancer Cells is different from Apoptotic Cell Death.
Citation: EUROPEAN JOURNAL OF NUCLEAR MEDICINE vol. 32 no. 3 p. 274-285
Publisher: SPRINGER
Publication Year: 2005
JRC N°: JRC30040
URI: http://publications.jrc.ec.europa.eu/repository/handle/JRC30040
Type: Articles in periodicals and books
Abstract: Purpose: Radioimmvmotherapy with a-parti-cle-emitting nuclides, such as 213Bi, is a promising con¬cept for the elimination of small tumour nodules or sin¬gle disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by 213Bi-immunoconjugates. Methods: Human gastric cancer cells (HSC45-M2) expressing d9-E-cad-herin were incubated with different levels of activity of 2i3Bi-d9MAb targeting d9-E-cadherin and 213Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay fol¬lowing fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as 213Bi-d9MAb. Activa¬tion of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and 213Bi-d9MAb was analysed via Western blotting. Results: Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with 213Bi-d9MAb the number of cells killed increased proportional to the applied activity concentra¬tion. Microscopically visible effects of a-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific 213Bi-d9MAb compared with unspecific 213Bi-d8MAb (not targeting dQ-E-cadherin) was not observed if the number of floating, i.e. unbound 213Bi-inimunoconjugates per cell exceeded 2x10*, most likely due to intense crossfire. In contrast to sorbitol-in-duced cell death, cell death triggered by 213Bi-immuno-conjugates was independent of caspase 3 activation and could not be inhibited by 2-VAD-fmk, known to suppress the apoptotic pathway. Conclusion: 213Bi-iinmunoconjü-gates seem to induce a mode of cell death different from apoptosis in HSC45-M2 cells.
JRC Directorate:Nuclear Safety and Security

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