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J Nucl Med. 2009; 50 (Supplement 2):637
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Oncology - Basic: Basic Science

Biomarkers and Radiation Effects

Analysis of DNA double-strand breaks in gastric cancer cells after treatment with 213Bi-immunoconjugates

Christof Seidl1, Annette Frank1, Birgit Pfost1, Alfred Morgenstern2, Frank Bruchertseifer2 and Reingard Senekowitsch-Schmidtke1

1 Dept. Nuclear Medicine, Technische Universitaet Muenchen, Munich, Germany 2 EC, JRC, Inst. Transuranium Elements, Karlsruhe, Germany

637

Objectives: To facilitate dosimetric calculations in {alpha}-emitter therapy, new concepts, preferably based on biological models, are needed. Since cytotoxicity of {alpha}-particles is due to induction of DNA double-strand breaks (DSBs), detection of DSBs should be a straightforward concept. At sites of DSBs histones H2AX are phosphorylated, resulting in {gamma}-H2AX. Using an antibody that specifically binds to {gamma}-H2AX, the numbers of DSBs can be correlated to the {alpha}-emitter activity applied. The aim of this study was to quantify DNA-DSBs in gastric cancer cells after incubation with 213Bi-immunoconjugates.

Methods: The monoclonal antibody d9MAb specifically binds to HSC45-M2 gastric cancer cells expressing mutant d9-E-cadherin. HSC45-M2 cells were incubated with different activity concentrations of tumor-specific 213Bi-d9MAb conjugates for 3 h (t1/2 = 46 min). At different time points after incubation {gamma}-H2AX was detected using immunofluorescence and Western blotting.

Results: Incubation of HSC45-M2 cells seeded in chamber slides with 1.48 GBq/ml caused massive formation of {gamma}-H2AX foci in the nuclei of treated cells that were not observed in the neighboring chamber incubated with PBS only. Thus, {gamma}-emission during 213Bi decay is unable to induce DSBs while {alpha}-particles triggered massive DSBs. Phosphorylation of histone H2AX in HSC45-M2 cells could also be demonstrated via Western blotting. Induction of {gamma}-H2AX foci was dependent on 213Bi-d9MAb activity concentration.

Conclusions: Detection of DSBs via {gamma}-H2AX foci is a promising concept to evaluate cytotoxicity and to estimate doses in 213Bi-immunotherapy.





This Article
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Right arrow Articles by Senekowitsch-Schmidtke, R.
PubMed
Right arrow Articles by Seidl, C.
Right arrow Articles by Senekowitsch-Schmidtke, R.