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Experimental and Molecular Therapeutics

Abstract 5771: Molecular radiation therapy: Targeting DNA damage response proteins

Cornelissen Bart, Veerle Kersemans, Sonali Darbar, Sean Smart and Katherine A. Vallis
Cornelissen Bart
1Univ. of Oxford, Oxford, United Kingdom.
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Veerle Kersemans
1Univ. of Oxford, Oxford, United Kingdom.
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Sonali Darbar
1Univ. of Oxford, Oxford, United Kingdom.
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Sean Smart
1Univ. of Oxford, Oxford, United Kingdom.
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Katherine A. Vallis
1Univ. of Oxford, Oxford, United Kingdom.
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DOI: 10.1158/1538-7445.AM10-5771 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

DNA damage is an early event after exposure of cells to many anti-cancer agents. Auger electron-emitting radiopharmaceuticals that localize at sites of DNA-double strand breaks (dsb) cause added damage, thus stimulating the formation of their own target and converting sublethal DNA lesions into irreparable damage. The histone H2A variant, H2AX, is phosphorylated on Ser139 (γH2AX) and forms foci at DNA-dsb. γH2AX foci are generally more numerous and resolve more slowly in cancer cells which are genomically unstable compared to normal cells. The aim of this study was to target γH2AX foci for molecular radiation therapy.

Methods: Anti-γH2AX (aγH2AX) or anti-mouse IgG (amIgG) monoclonal antibodies were modified by addition of a nuclear localizing signal (NLS)-containing cell penetrating peptide, TAT, through N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling. Cyclic diethylenetriaminepentaacetic dianhydride (cDTPA) was added for radiolabeling with 111-indium. Fluorophore AlexaFluor 488-labelled variants of both radioimmunoconjugates (RICs) were also prepared.

Results: Using confocal microscopy, AF488-aγH2AX-TAT but not AF488-amIgG-TAT was found to colocalize with γH2AX-foci in cells exposed to X-Ray irradiation (IR) (4 Gy). To evaluate cellular retention of RICs, MDA-MB-468 or MDA-MB-231/H2N human breast cancer cells were treated with 111In-aγH2AX-TAT or 111In-amIgG-TAT (0.5 µg, 0.1 MBq/µg) and exposed to IR (4 Gy) or bleomycin (20 µg/mL). 111In was retained 16-fold longer in IR- or bleomycin-treated cells exposed to 111In-aγH2AX-TAT compared to control cells exposed to 111In-aγH2AX-TAT. 111In-aγH2AX-TAT (6 MBq/µg) caused amplification of both IR-induced DNA-dsb (evaluated by γH2AX foci number and the neutral comet assay [NCA]) and clustered DNA damage (evaluated by NCA plus glycosylases). In clonogenic assays, the combination of 111In-aγH2AX-TAT plus IR or bleomycin was significantly more cytotoxic than either agent alone and more cytotoxic than 111In-amIgG-Tat plus IR or bleomycin alone. In in vivo experiments, uptake of 111In-aγH2AX-TAT, but not 111In-amIgG-TAT, was up to 6-fold greater in MDA-MB-231/H2N xenografts exposed to IR (4 or 10 Gy) and in bleomycin-treated mice compared to untreated controls. The volume doubling time of MDA-MB-231/H2N xenografts increased 13-fold (p < 0.05) in animals treated with IR (10 Gy) plus 111In-aγH2AX-TAT (10 µg, 6 MBq/µg) compared to those exposed to IR or 111In-αγH2AX-TAT alone.

Conclusion: 111In-aγH2AX-TAT is a novel radiopharmaceutical that amplifies DNA-damage and enhances the cytotoxicity of IR and chemotherapy in vitro and in vivo.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5771.

  • ©2010 American Association for Cancer Research
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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract 5771: Molecular radiation therapy: Targeting DNA damage response proteins
Cornelissen Bart, Veerle Kersemans, Sonali Darbar, Sean Smart and Katherine A. Vallis
Cancer Res April 15 2010 (70) (8 Supplement) 5771; DOI: 10.1158/1538-7445.AM10-5771

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Abstract 5771: Molecular radiation therapy: Targeting DNA damage response proteins
Cornelissen Bart, Veerle Kersemans, Sonali Darbar, Sean Smart and Katherine A. Vallis
Cancer Res April 15 2010 (70) (8 Supplement) 5771; DOI: 10.1158/1538-7445.AM10-5771
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Cancer Research Online ISSN: 1538-7445
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