| Radiobiological effects of hypoxia-dependent uptake of 64Cu-ATSM: enhanced DNA damage and cytotoxicity in hypoxic cells. | |
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MedLine Citation:
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PMID: 19915836 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: Hypoxia occurs frequently in cancers and can lead to therapeutic resistance due to poor perfusion and loss of the oxygen enhancement effect. (64)Cu-ATSM has shown promise as a hypoxia diagnostic agent due to its selective uptake and retention in hypoxic cells and its emission of positrons for PET imaging. (64)Cu also emits radiotoxic Auger electrons and beta(-) particles and may therefore exhibit therapeutic potential when concentrated in hypoxic tissue. METHODS: MCF-7 cells were treated with 0-10 MBq/ml (64)Cu-ATSM under differing oxygen conditions ranging from normoxia to severe hypoxia. Intracellular response to hypoxia was measured using Western blotting for expression of HIF-1alpha, while cellular accumulation of (64)Cu was measured by gamma counting. DNA damage and cytotoxicity were measured with, respectively, the Comet assay and clonogenic survival. RESULTS: (64)Cu-ATSM uptake in MCF-7 cells increased as atmospheric oxygen decreased (up to 5.6 Bq/cell at 20.9% oxygen, 10.4 Bq/cell at 0.1% oxygen and 26.0 Bq/cell at anoxia). Toxicity of (64)Cu-ATSM in MCF-7 cells also increased as atmospheric oxygen decreased, with survival of 9.8, 1.5 and 0% in cells exposed to 10 MBq/ml at 20.9, 0.1 and 0% oxygen. The Comet assay revealed a statistically significant increase in (64)Cu-ATSM-induced DNA damage under hypoxic conditions. CONCLUSION: The results support a model in which hypoxia-enhanced uptake of radiotoxic (64)Cu induces sufficient DNA damage and toxicity to overcome the documented radioresistance in hypoxic MCF-7 cells. This suggests that (64)Cu-ATSM and related complexes have potential for targeted radionuclide therapy of hypoxic tumours. |
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Authors:
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Amanda J Weeks; Rowena L Paul; Paul K Marsden; Philip J Blower; Daniel R Lloyd |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-11-14 |
Journal Detail:
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Title: European journal of nuclear medicine and molecular imaging Volume: 37 ISSN: 1619-7089 ISO Abbreviation: Eur. J. Nucl. Med. Mol. Imaging Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-07-14 Completed Date: 2010-12-01 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101140988 Medline TA: Eur J Nucl Med Mol Imaging Country: Germany |
Other Details:
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Languages: eng Pagination: 330-8 Citation Subset: IM |
Affiliation:
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School of Biosciences, University of Kent, Canterbury, Kent, UK. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Biological Transport Cell Hypoxia Cell Line, Tumor Cell Survival / drug effects, radiation effects DNA Damage* Humans Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Organometallic Compounds / diagnostic use, metabolism*, pharmacology* Oxygen / metabolism Radiobiology* Thiosemicarbazones / diagnostic use, metabolism*, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Organometallic Compounds; 0/Thiosemicarbazones; 0/copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); 7782-44-7/Oxygen |
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