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Meeting ReportOncology - Basic: Basic Science

Amplification of IR-induced DNA damage by Auger electron treatment with TAT-radioimmunoconjugates

Bart Cornelissen, Sonali Darbar, Kate Sleeth, Veerle Kersemans and Katherine Vallis
Journal of Nuclear Medicine May 2009, 50 (supplement 2) 638;
Bart Cornelissen
1University of Oxford, MRC/CRUK Gray Institute for Radiation Oncology and Biology, Oxford, United Kingdom
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Sonali Darbar
1University of Oxford, MRC/CRUK Gray Institute for Radiation Oncology and Biology, Oxford, United Kingdom
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Kate Sleeth
1University of Oxford, MRC/CRUK Gray Institute for Radiation Oncology and Biology, Oxford, United Kingdom
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Veerle Kersemans
1University of Oxford, MRC/CRUK Gray Institute for Radiation Oncology and Biology, Oxford, United Kingdom
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Katherine Vallis
1University of Oxford, MRC/CRUK Gray Institute for Radiation Oncology and Biology, Oxford, United Kingdom
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Abstract

638

Objectives The most deleterious DNA lesions caused by ionizing radiation are double strand breaks (DSB). We hypothesise that it is possible to amplify DSB damage using a novel Auger electron-emitting radiopharmaceutical, 111In-DTPA-anti-γH2AX-TAT, which targets γH2AX foci at sites of DSB. TAT-peptide conjugation confers cell-penetrating and nuclear localisation properties to the radioimmunoconjugate.

Methods 111In-DTPA-anti-γH2AX-TAT was synthesised using EDC/NHS chemistry for TAT-peptide linkage and cDTPA coupling for 111In chelation. Internalisation and retention assays were performed on a panel of irradiated (up to 10Gy) and non-irradiated breast cancer cells, using 111In-DTPA-mouseIgG-TAT as a non-specific control. Clonogenic survival and neutral comet assays were performed to study amplification of cell kill.

Results TAT:IgG ratio was 5:1, DTPA:IgG ratio was 1.5:1. Radiochemical yield was 89% and radiochemical purity was >97%. The retention of 111In-DTPA-anti-γH2AX-TAT in MDA-MB-468 cells was increased following IR (4 Gy) compared to non-irradiated controls (80 vs. 20 % retention at 4 h, respectively). The retention of 111In-DTPA-mouseIgG-TAT was similar to that of 111In-DTPA-anti-γH2AX-TAT in control cells but was unaffected by IR. 111In-DTPA-anti-γH2AX-TAT but not 111In-DTPA-mouseIgG-TAT caused decreased clonogenic survival of cells exposed to IR. Both 111In-DTPA-anti-γH2AX-TAT and 111In-DTPA-mouseIgG-TAT alone caused minimal cell kill. Comet assays indicated augmentation of DNA damage in cells exposed to IR plus 111In-DTPA-anti-γH2AX-TAT.

Conclusions 111In-DTPA-anti-γH2AX-TAT results in amplification of DNA DSB damage in cancer cells.

  • © 2009 by Society of Nuclear Medicine
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Journal of Nuclear Medicine
Vol. 50, Issue supplement 2
May 2009
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Amplification of IR-induced DNA damage by Auger electron treatment with TAT-radioimmunoconjugates
Bart Cornelissen, Sonali Darbar, Kate Sleeth, Veerle Kersemans, Katherine Vallis
Journal of Nuclear Medicine May 2009, 50 (supplement 2) 638;

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Amplification of IR-induced DNA damage by Auger electron treatment with TAT-radioimmunoconjugates
Bart Cornelissen, Sonali Darbar, Kate Sleeth, Veerle Kersemans, Katherine Vallis
Journal of Nuclear Medicine May 2009, 50 (supplement 2) 638;
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