4-(3-fluoropropyl)glutamic acid; Amino Acid Transport System y+; Fluorine Radioisotopes; Glutamates; Radiopharmaceuticals; SLC7A11 protein, human; Amino Acid Transport System y+/metabolism; Fluorine Radioisotopes/metabolism; Glutamates/metabolism; Positron-Emission Tomography/methods; Radiopharmaceuticals/metabolism; Positron-Emission Tomography; Oncology; Cancer Research
Abstract :
[en] The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc - maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here, we show that tumor cell retention of a system xc --specific PET radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment. SIGNIFICANCE: [18F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy.See related commentary by Lee et al., p. 701.
Disciplines :
Chemistry Radiology, nuclear medicine & imaging
Author, co-author :
McCormick, Patrick N; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom
Greenwood, Hannah E; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom
Glaser, Matthias; Institute of Nuclear Medicine and Department of Chemistry, University College London, London, United Kingdom
Maddocks, Oliver D K ; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Gendron, Thibault ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique-nucléaire ; Institute of Nuclear Medicine and Department of Chemistry, University College London, London, United Kingdom
Sander, Kerstin; Institute of Nuclear Medicine and Department of Chemistry, University College London, London, United Kingdom
Gowrishankar, Gayatri; Department of Radiology, Molecular Imaging Program, Stanford University, Palo Alto, Stanford, California
Hoehne, Aileen; Department of Radiology, Molecular Imaging Program, Stanford University, Palo Alto, Stanford, California
Zhang, Tong; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
Shuhendler, Adam J; Department of Radiology, Molecular Imaging Program, Stanford University, Palo Alto, Stanford, California
Lewis, David Y; Department of Radiology, Molecular Imaging Program, Stanford University, Palo Alto, Stanford, California
Berndt, Mathias; Life Molecular Imaging GmbH, Berlin, Germany
Koglin, Norman; Life Molecular Imaging GmbH, Berlin, Germany
Lythgoe, Mark F; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom
Gambhir, Sanjiv S; Department of Radiology, Molecular Imaging Program, Stanford University, Palo Alto, Stanford, California ; Department of Bioengineering, Department of Materials Science and Engineering, Bio-X, Stanford University, Palo Alto, Stanford, California
Årstad, Erik; Institute of Nuclear Medicine and Department of Chemistry, University College London, London, United Kingdom
Witney, Timothy H ; Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom. tim.witney@kcl.ac.uk
Wellcome Trust [US] CRUK - Cancer Research UK [GB] EPSRC - Engineering and Physical Sciences Research Council [GB]
Funding text :
N. Koglin has ownership interest (including stocks and patents) in Piramal Imaging/Life Molecular Imaging. T.H. Witney is a consultant at Cellsight Technologies Inc. and reports receiving a commercial research grant from Piramal Imaging/Life Molecular Imaging. S.S. Gambhir is a consultant/advisory board member for Piramal Imaging/Life Molecular Imaging and reports receiving a commercial research grant from Piramal Imaging/Life Molecular Imaging. E. Årstad reports receiving a commercial research grant from Mallinckrodt. No potential conflicts of interest were disclosed by the other authors.The authors would like to thank Andrew Stephens and Stephen Patrick for helpful theoretical discussions, Bernadette Schneider for technical support regarding [18F]FSPG radiochemistry, William Day for help with flow cytometric experiments, and May Zaw-Thin for assistance during PET scanning. The authors also acknowledge the SCi3 Small Animal Imaging Service Center, which was used to create data presented in this study, specifically, Tim Doyle and Israt Alam for their valuable assistance. This study was funded through a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (107610/Z/15/Z) and the Cancer Research UK-UCL Centre (C416/A18088 to T.H. Witney), the CRUK & EPSRC
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