Weeks, A.J. and Paul, R.L. and Marsden, P.L. and Blower, P.J. and Lloyd, D.R. (2010) Radiobiological effects of hypoxia-dependent uptake of (64)Cu-ATSM: enhanced DNA damage and cytotoxicity in hypoxic cells. European Journal of Nuclear Medicine and Molecular Imaging, 37 (2). pp. 330-338. ISSN 1619-7089.
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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.
|Subjects:||R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences > Biomedical Research Group|
|Depositing User:||Dan Lloyd|
|Date Deposited:||29 Jun 2011 13:26|
|Last Modified:||09 May 2012 09:08|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/23738 (The current URI for this page, for reference purposes)|
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