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Abstract
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.

Author information

McCormick PN1, Greenwood HE1, Glaser M2, Maddocks ODK3, Gendron T2, Sander K2, Gowrishankar G4, Hoehne A4, Zhang T3, Shuhendler AJ4, Lewis DY4, Berndt M5, Koglin N5, Lythgoe MF1, Gambhir SS4,6, Årstad E2, Witney TH7.
1
Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom.
2
Institute of Nuclear Medicine and Department of Chemistry, University College London, London, United Kingdom.
3
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
4
Department of Radiology, Molecular Imaging Program, Stanford University, Palo Alto, Stanford, California.
5
Life Molecular Imaging GmbH, Berlin, Germany.
6
Department of Bioengineering, Department of Materials Science and Engineering, Bio-X, Stanford University, Palo Alto, Stanford, California.
7
Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom. tim.witney@kcl.ac.uk.