Thymidine metabolism as a confounding factor for 3'-Deoxy-3'-18F-fluorothymidine uptake after therapy in a colorectal cancer model

Sonja Schelhaas, Lydia Wachsmuth, Sven Hermann, Natascha Rieder, Astrid Heller, Kathrin Heinzmann, Davina J. Honess, Donna Michelle Smith, Inga B. Fricke, Nathalie Just, Sabrina Doblas, Ralph Sinkus, Christian Döring, Klaus P. Schäfers, John R. Griffiths, Cornelius Faber, Richard Schneider, Eric O. Aboagye, Andreas H. Jacobs*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Noninvasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential PET and diffusion-weighted MRI to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods: Tumor-bearing CD1 nude mice, engrafted with FOLFOX-sensitive Colo205 colorectal cancer xenografts, were treated with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) weekly. On days 1, 2, 6, 9, and 13 of therapy, tumors were assessed by in vivo imaging and ex vivo analyses. In addition, HCT116 xenografts, which did not respond to the FOLFOX treatment, were imaged on day 1 of therapy. Results: In Colo205 xenografts, FOLFOX induced a profound increase in uptake of the proliferation PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) accompanied by increases in markers for proliferation (Ki-67, thymidine kinase 1) and for activated DNA damage response (γH2AX), whereas the effect on cell death was minimal. Because tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrated that 18F-FLT PET can noninvasivelymonitor cancer treatment-inducedmolecular alterations, including thymidine metabolism and DNA damage response. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements.

Original languageEnglish
Pages (from-to)1063-1069
Number of pages7
JournalJournal of Nuclear Medicine
Volume59
Issue number7
Early online date23 Feb 2018
DOIs
Publication statusPublished - 1 Jul 2018

Keywords

  • F-FLT PET
  • Combination cancer therapy
  • DW-MRI
  • Small-animal imaging

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