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.
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.
Authors: A Hartmann; E Agurell; C Beevers; S Brendler-Schwaab; B Burlinson; P Clay; A Collins; A Smith; G Speit; V Thybaud; R R Tice Journal: Mutagenesis Date: 2003-01 Impact factor: 3.000
Authors: Paul Burgman; Joseph A O'Donoghue; Jason S Lewis; Michael J Welch; John L Humm; C Clifton Ling Journal: Nucl Med Biol Date: 2005-08 Impact factor: 2.408
Authors: Farrokh Dehdashti; Perry W Grigsby; Jason S Lewis; Richard Laforest; Barry A Siegel; Michael J Welch Journal: J Nucl Med Date: 2008-01-16 Impact factor: 10.057
Authors: K Tateishi; U Tateishi; M Sato; S Yamanaka; H Kanno; H Murata; T Inoue; N Kawahara Journal: AJNR Am J Neuroradiol Date: 2012-06-14 Impact factor: 3.825
Authors: Richard Southworth; Rafael Torres Martin de Rosales; Levente K Meszaros; Michelle T Ma; Gregory E D Mullen; Gilbert Fruhwirth; Jennifer D Young; Cinzia Imberti; Julia Bagunya-Torres; Erica Andreozzi; Philip J Blower Journal: Adv Inorg Chem Date: 2015-11-16 Impact factor: 3.282
Authors: Christian Wulbrand; Christof Seidl; Florian C Gaertner; Frank Bruchertseifer; Alfred Morgenstern; Markus Essler; Reingard Senekowitsch-Schmidtke Journal: PLoS One Date: 2013-05-28 Impact factor: 3.240
Authors: Elizabeth A Ballegeer; Nicole J Madrill; Kevin L Berger; Dalen W Agnew; Elizabeth A McNiel Journal: BMC Cancer Date: 2013-04-30 Impact factor: 4.430