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Relationship Between Induction of Phosphorylated H2AX and Survival in Breast Cancer Cells Exposed to ¹¹¹In-DTPA-hEGF

¹ Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; ² Division of Applied Molecular Oncology, Ontario Cancer Institute, Toronto, Ontario, Canada; ³ Division of Nuclear Medicine, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; ⁴ Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada; and ⁵ Radiation Oncology and Biology, University of Oxford, Oxford, United Kingdom

Correspondence: For correspondence or reprints contact: Katherine A. Vallis, Radiobiology Research Institute, Churchill Hospital, Oxford, OX3 7LJ, U.K. E-mail: katherine.vallis{at}rob.ox.ac.uk

The Auger electron–emitting radiopharmaceutical ¹¹¹In-diethylenetriaminepentaacetic acid human epidermal growth factor (¹¹¹In-DTPA-hEGF) binds the epidermal growth factor receptor (EGFR), is internalized, and translocates to the nucleus. The purpose of this study was to investigate the relationship between EGFR expression, DNA damage, and cytotoxicity in cells exposed to ¹¹¹In-DTPA-hEGF. Methods: Breast cancer cell lines with a range of EGFR expression levels were exposed to ¹¹¹In-DTPA-hEGF or -radiation. The cell lines (followed by number of EGFR per cell in parentheses) were MDA-MB-468 (1.3 x 10⁶), MDA-MB-231 (1.3 x 10⁵), and MCF-7 (1.5 x 10⁴). The proportion of radioactivity partitioning into the nucleus was measured by cell fractionation. DNA double-strand breaks were evaluated using the -H2AX assay. Clonogenic survival assays were used to measure cytotoxicity. Results: All data are presented as mean ± SD. The amount of ¹¹¹In-DTPA-hEGF that translocated to the nucleus (in mBq/nucleus) in MDA-MB-468, MDA-MB-231, and MCF-7 cells incubated with ¹¹¹In-DTPA-hEGF (5.2 MBq/mL, 43 nM) for 20 h was 131 ± 6, 8.1 ± 0.1, and 1.1 ± 0.9, respectively. The number of -H2AX foci per nucleus was 35 ± 15, 19 ± 10, and 1.7 ± 0.3, respectively. A reduction in the surviving fraction (SF) in MDA-MB-468 (0.013 ± 0.001) and MDA-MB-231 (0.5 ± 0.1) but not in MCF-7 cells after exposure to ¹¹¹In-DTPA-hEGF (5.2 MBq/mL, 43 nM) for 20 h has been demonstrated. The SF of MDA-MB-468 cells after exposure to DTPA-EGF (43 nM) and ¹¹¹In-acetate (5.2 MBq/mL) for 20 h was 0.5 ± 0.1 and 0.53 ± 0.05, respectively. MDA-MB-468 was the most sensitive of the cell lines to -irradiation, with an SF after 2 Gy of 0.45 ± 0.04, compared with 0.7 ± 0.1 and 0.8 ± 0.1 for MCF-7 and MDA-MB-231, respectively. The number of -H2AX foci per nucleus in MDA-MB-468 cells correlated with the concentration, specific activity, and incubation time of ¹¹¹In-DTPA-hEGF. Conclusion: DNA damage caused by ¹¹¹In-DTPA-hEGF correlates with the EGFR expression level of the exposed cells and with concentration, specific activity, and incubation time of ¹¹¹In-DTPA-hEGF. The -H2AX assay may be a useful biomarker to predict and monitor the outcome of treatment with ¹¹¹In-DTPA-hEGF.

Key Words: Auger electrons • H2AX • ¹¹¹In-DTPA-hEGF • epidermal growth factor receptor

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

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