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Influx rate of 18F-fluoroaminosuberic acid reflects cystine/glutamate antiporter expression in tumour xenografts

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Abstract

Purpose

18F-fluoroaminosuberic acid (18F-FASu) is a recently developed amino acid tracer for positron emission tomography (PET) of oxidative stress that may offer improved tumour assessment over the conventional tracer 18F-fluorodeoxyglucose (18F-FDG). Our aim was to evaluate and relate dynamic 18F-FASu and 18F-FDG uptake with pharmacokinetic modelling to transporter protein expression levels in a panel of diverse tumour xenograft lines.

Methods

Four different tumour xenograft lines were implanted in female athymic nude mice: MAS98.12 and HBCx3 (breast), TPMX (osteosarcoma) and A549 (lung). Dynamic PET over 60 min was performed on a small animal unit. The time–activity curves (TACs) for 18F-FASu and 18F-FDG in individual tumours were used to extract early (SUVE; 2 min p.i.) and late (SUVL; 55 min p.i.) standardised uptake values. Pharmacokinetic two-tissue compartment models were applied to the TACs to estimate rate constants K1–k4 and blood volume fraction vB. Relative levels of cystine/glutamate antiporter subunit xCT were assessed by western blotting, and expression of GLUT1 and CD31 by immunohistochemistry.

Results

18F-FASu showed higher SUVE, whilst 18F-FDG exhibited higher SUVL. Influx rate K1 for 18F-FASu was significantly correlated with xCT levels (p = 0.001) and was significantly higher than K1 for 18F-FDG (p < 0.001). K1 for 18F-FDG was significantly correlated with GLUT1 levels (p = 0.002). vB estimated from 18F-FASu and 18F-FDG TACs was highly consistent and significantly correlated (r = 0.85, p < 0.001). Two qualitatively different 18F-FASu uptake profiles were identified: type α with low xCT expression and low K1 (A549 and HBCx3), and type β with high xCT expression and high K1 (MAS98.12 and TPMX).

Conclusion

The influx rate of 18F-FASu reflects xCT activity in tumour xenografts. Dynamic PET with pharmacokinetic modelling is needed to fully appraise 18F-FASu distribution routes.

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Funding

This study was funded by the University of Oslo (convergence grants) and the Norwegian Cancer Society (grant 6871141-2015).

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Authors and Affiliations

  1. Department of Physics, University of Oslo, P.O. Box 1048 Blindern, 0316, Oslo, Norway

    Kathinka E. Pitman & Eirik Malinen

  2. Department of Medical Physics, Oslo University Hospital, Oslo, Norway

    Kathinka E. Pitman & Eirik Malinen

  3. Department of Chemistry, University of Oslo, P.O. Box 1048 Blindern, 0316, Oslo, Norway

    Santosh R. Alluri & Patrick J. Riss

  4. Department of Tumour Biology, Oslo University Hospital, Oslo, Norway

    Alexander Kristian

  5. Department of Radiation Biology, Oslo University Hospital, Oslo, Norway

    Eva-Katrine Aarnes & Heidi Lyng

Authors
  1. Kathinka E. Pitman
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Correspondence to Eirik Malinen.

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This article is part of the Topical Collection on Advanced Image Analyses (Radiomics and Artificial Intelligence)

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Pitman, K.E., Alluri, S.R., Kristian, A. et al. Influx rate of 18F-fluoroaminosuberic acid reflects cystine/glutamate antiporter expression in tumour xenografts. Eur J Nucl Med Mol Imaging 46, 2190–2198 (2019). https://doi.org/10.1007/s00259-019-04375-8

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