Milena Čolović1,2, Hua Yang1, Helen Merkens2, Nadine Colpo2, François Bénard3,4,5, Paul Schaffer6,7,8. 1. Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada. 2. British Columbia Cancer Research Centre, Vancouver, BC, Canada. 3. British Columbia Cancer Research Centre, Vancouver, BC, Canada. fbenard@bccrc.ca. 4. Molecular Oncology, British Columbia Cancer Research Centre, 675 W 10th Ave, Vancouver, BC, V5Z 1L3, Canada. fbenard@bccrc.ca. 5. Department of Radiology, Faculty of Medicine, University of British Columbia, Vancouver, Canada. fbenard@bccrc.ca. 6. Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada. pschaffer@triumf.ca. 7. Department of Radiology, Faculty of Medicine, University of British Columbia, Vancouver, Canada. pschaffer@triumf.ca. 8. Department of Chemistry, Faculty of Science, Simon Fraser University, Vancouver, Canada. pschaffer@triumf.ca.
Abstract
PURPOSE: The system xC- transporter is upregulated in cancer cells in response to oxidative stress (OS). 5-[18F]fluoroaminosuberic acid ([18F]FASu) has been reported as a novel positron emission tomography (PET) imaging agent, targeting system xC-. The goal of this study was to evaluate the utility of [18F]FASu in monitoring cellular response to diethyl maleate (DEM) and radiation-induced OS fluctuations. PROCEDURES: [18F]FASu uptake by breast cancer cells was studied in correlation to OS biomarkers: glutathione (GSH) and reactive oxygen species (ROS), as well as transcriptional and translational levels of xCT (the functional subunit of xC-). System xC- inhibitor, sulfasalazine (SSZ), and small interfering RNA (siRNA) knockdown were used as negative controls. Radiotracer uptake was evaluated in three breast cancer models: MDA-MB-231, MCF-7, and ZR-75-1, at two-time points (1 h and 16 h) following OS induction. In vivo [18F]FASu imaging and biodistribution were performed using MDA-MB-231 xenograft-bearing mice at 16 and 24 h post-radiation treatment. RESULTS: [18F]FASu uptake was positively correlated to intracellular GSH and SLC7A11 expression levels, and radiotracer uptake was induced both by radiation treatment and by DEM at time points longer than 3 h. In an in vivo setting, there was no statistically significant uptake difference between irradiated and control tumors. CONCLUSION: [18F]FASu is a specific system xC- PET radiotracer and as such it can be used to monitor system xC- activity due to OS. As such, [18F]FASu has the potential to be used in therapy response monitoring by PET. Further optimization is required for in vivo application.
PURPOSE: The system xC- transporter is upregulated in cancer cells in response to oxidative stress (OS). 5-[18F]fluoroaminosuberic acid ([18F]FASu) has been reported as a novel positron emission tomography (PET) imaging agent, targeting system xC-. The goal of this study was to evaluate the utility of [18F]FASu in monitoring cellular response to diethyl maleate (DEM) and radiation-induced OS fluctuations. PROCEDURES: [18F]FASu uptake by breast cancer cells was studied in correlation to OS biomarkers: glutathione (GSH) and reactive oxygen species (ROS), as well as transcriptional and translational levels of xCT (the functional subunit of xC-). System xC- inhibitor, sulfasalazine (SSZ), and small interfering RNA (siRNA) knockdown were used as negative controls. Radiotracer uptake was evaluated in three breast cancer models: MDA-MB-231, MCF-7, and ZR-75-1, at two-time points (1 h and 16 h) following OS induction. In vivo [18F]FASu imaging and biodistribution were performed using MDA-MB-231 xenograft-bearing mice at 16 and 24 h post-radiation treatment. RESULTS:[18F]FASu uptake was positively correlated to intracellular GSH and SLC7A11 expression levels, and radiotracer uptake was induced both by radiation treatment and by DEM at time points longer than 3 h. In an in vivo setting, there was no statistically significant uptake difference between irradiated and control tumors. CONCLUSION:[18F]FASu is a specific system xC- PET radiotracer and as such it can be used to monitor system xC- activity due to OS. As such, [18F]FASu has the potential to be used in therapy response monitoring by PET. Further optimization is required for in vivo application.
Authors: Susanne Müerköster; Alexander Arlt; Maike Witt; André Gehrz; Sieglinde Haye; Christina March; Frauke Grohmann; Kai Wegehenkel; Holger Kalthoff; Ulrich R Fölsch; Heiner Schäfer Journal: Int J Cancer Date: 2003-04-20 Impact factor: 7.396
Authors: Maximilian Diehn; Robert W Cho; Neethan A Lobo; Tomer Kalisky; Mary Jo Dorie; Angela N Kulp; Dalong Qian; Jessica S Lam; Laurie E Ailles; Manzhi Wong; Benzion Joshua; Michael J Kaplan; Irene Wapnir; Frederick M Dirbas; George Somlo; Carlos Garberoglio; Benjamin Paz; Jeannie Shen; Sean K Lau; Stephen R Quake; J Martin Brown; Irving L Weissman; Michael F Clarke Journal: Nature Date: 2009-04-09 Impact factor: 49.962
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