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

  • Kathinka E. Pitman
  • Santosh R. Alluri
  • Alexander Kristian
  • Eva-Katrine Aarnes
  • Heidi Lyng
  • Patrick J. Riss
  • Eirik MalinenEmail author
Original Article
  • 43 Downloads
Part of the following topical collections:
  1. Advanced Image Analyses (Radiomics and Artificial Intelligence)

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.

Keywords

Cancer Xenograft Mouse model System XC xCT 18F-fluoroaminosuberic acid 18F-FDG Dynamic PET Pharmacokinetic modelling Oxidative stress 

Notes

Funding

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

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

259_2019_4375_MOESM1_ESM.pdf (628 kb)
ESM 1 (PDF 627 kb)
259_2019_4375_MOESM2_ESM.docx (3.8 mb)
ESM 2 (DOCX 3938 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PhysicsUniversity of OsloOsloNorway
  2. 2.Department of Medical PhysicsOslo University HospitalOsloNorway
  3. 3.Department of ChemistryUniversity of OsloOsloNorway
  4. 4.Department of Tumour BiologyOslo University HospitalOsloNorway
  5. 5.Department of Radiation BiologyOslo University HospitalOsloNorway

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