Amplification of DNA damage by a γH2AX-targeted radiopharmaceutical
111In-DTPA-anti-γH2AX-Tat, which combines an anti-γH2AX antibody with a cell-penetrating peptide, Tat, and the Auger electron-emitting radioisotope, 111In, targets the DNA damage signalling protein, γH2AX, and has potential as a probe for imaging DNA damage in vivo. The goal of this study was to inv...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2012
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| _version_ | 1826277792019382272 |
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| author | Cornelissen, B Darbar, S Kersemans, V Allen, D Falzone, N Barbeau, J Smart, S Vallis, K |
| author_facet | Cornelissen, B Darbar, S Kersemans, V Allen, D Falzone, N Barbeau, J Smart, S Vallis, K |
| author_sort | Cornelissen, B |
| collection | OXFORD |
| description | 111In-DTPA-anti-γH2AX-Tat, which combines an anti-γH2AX antibody with a cell-penetrating peptide, Tat, and the Auger electron-emitting radioisotope, 111In, targets the DNA damage signalling protein, γH2AX, and has potential as a probe for imaging DNA damage in vivo. The goal of this study was to investigate whether 111In-DTPA-anti-γH2AX-Tat labelled to high specific activity (6MBq/μg) can amplify treatment-related DNA damage for therapeutic gain. Methods: MDA-MB-468 and MDA-MB-231/H2N (231-H2N) breast cancer cells were incubated with 111In-DTPA-anti-γH2AX-Tat (3MBq, 6MBq/μg) or a control radioimmunoconjugate, 111In-DTPA-mIgG-Tat, and exposed to IR or bleomycin. DNA damage was studied by counting γH2AX foci and by neutral comet assay. Cytotoxicity was evaluated using clonogenic assays. 111In-DTPA-anti-γH2AX-Tat was administered intravenously to 231-H2N-xenograft-bearing Balb/c nu/nu mice in tumor growth inhibition studies. Results: The number of γH2AX foci was greater after exposure of cells to IR (10Gy) plus 111In-DTPA-anti-γH2AX-Tat compared to IR alone (20.6±2.5 versus 10.4±2.3 foci/cell; P<.001).111In-DTPA-anti-γH2AX-Tat resulted in a reduced surviving fraction in cells co-treated with IR (4Gy) versus IR alone (5.2%±0.9% versus 47.8%±2.8%; P<.001). Similarly, bleomycin (25-200μg/mL) plus 111In-DTPA-anti-γH2AX-Tat resulted in a lower SF compared to bleomycin alone. The combination of a single exposure to IR (10Gy) plus 111In-DTPA-anti-γH2AX-Tat significantly decreased the growth rate of 231-H2N xenografts in vivo compared to either 111In-DTPA-anti-γH2AX-Tat or IR alone (-0.002±0.004 versus 0.036±0.011 and 0.031±0.014mm3/day, respectively, P<.001). Conclusion: 111In-DTPA-anti-γH2AX-Tat amplifies anticancer treatment-related DNA damage in vitro and has a potent anti-tumor effect when combined with IR in vivo. © 2012 Elsevier Inc.. |
| first_indexed | 2024-03-06T23:34:14Z |
| format | Journal article |
| id | oxford-uuid:6d1b4169-edea-4ced-9a67-11d68af6a4eb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:34:14Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:6d1b4169-edea-4ced-9a67-11d68af6a4eb2022-03-26T19:15:31ZAmplification of DNA damage by a γH2AX-targeted radiopharmaceuticalJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6d1b4169-edea-4ced-9a67-11d68af6a4ebEnglishSymplectic Elements at Oxford2012Cornelissen, BDarbar, SKersemans, VAllen, DFalzone, NBarbeau, JSmart, SVallis, K111In-DTPA-anti-γH2AX-Tat, which combines an anti-γH2AX antibody with a cell-penetrating peptide, Tat, and the Auger electron-emitting radioisotope, 111In, targets the DNA damage signalling protein, γH2AX, and has potential as a probe for imaging DNA damage in vivo. The goal of this study was to investigate whether 111In-DTPA-anti-γH2AX-Tat labelled to high specific activity (6MBq/μg) can amplify treatment-related DNA damage for therapeutic gain. Methods: MDA-MB-468 and MDA-MB-231/H2N (231-H2N) breast cancer cells were incubated with 111In-DTPA-anti-γH2AX-Tat (3MBq, 6MBq/μg) or a control radioimmunoconjugate, 111In-DTPA-mIgG-Tat, and exposed to IR or bleomycin. DNA damage was studied by counting γH2AX foci and by neutral comet assay. Cytotoxicity was evaluated using clonogenic assays. 111In-DTPA-anti-γH2AX-Tat was administered intravenously to 231-H2N-xenograft-bearing Balb/c nu/nu mice in tumor growth inhibition studies. Results: The number of γH2AX foci was greater after exposure of cells to IR (10Gy) plus 111In-DTPA-anti-γH2AX-Tat compared to IR alone (20.6±2.5 versus 10.4±2.3 foci/cell; P<.001).111In-DTPA-anti-γH2AX-Tat resulted in a reduced surviving fraction in cells co-treated with IR (4Gy) versus IR alone (5.2%±0.9% versus 47.8%±2.8%; P<.001). Similarly, bleomycin (25-200μg/mL) plus 111In-DTPA-anti-γH2AX-Tat resulted in a lower SF compared to bleomycin alone. The combination of a single exposure to IR (10Gy) plus 111In-DTPA-anti-γH2AX-Tat significantly decreased the growth rate of 231-H2N xenografts in vivo compared to either 111In-DTPA-anti-γH2AX-Tat or IR alone (-0.002±0.004 versus 0.036±0.011 and 0.031±0.014mm3/day, respectively, P<.001). Conclusion: 111In-DTPA-anti-γH2AX-Tat amplifies anticancer treatment-related DNA damage in vitro and has a potent anti-tumor effect when combined with IR in vivo. © 2012 Elsevier Inc.. |
| spellingShingle | Cornelissen, B Darbar, S Kersemans, V Allen, D Falzone, N Barbeau, J Smart, S Vallis, K Amplification of DNA damage by a γH2AX-targeted radiopharmaceutical |
| title | Amplification of DNA damage by a γH2AX-targeted radiopharmaceutical |
| title_full | Amplification of DNA damage by a γH2AX-targeted radiopharmaceutical |
| title_fullStr | Amplification of DNA damage by a γH2AX-targeted radiopharmaceutical |
| title_full_unstemmed | Amplification of DNA damage by a γH2AX-targeted radiopharmaceutical |
| title_short | Amplification of DNA damage by a γH2AX-targeted radiopharmaceutical |
| title_sort | amplification of dna damage by a γh2ax targeted radiopharmaceutical |
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