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Thymidine Metabolism as Confounding Factor of 3'-Deoxy-3'-[18F]Fluorothymidine Uptake after Therapy in a Colorectal Cancer Model.

Accepted version
Peer-reviewed

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Authors

Schelhaas, Sonja 
Wachsmuth, Lydia 
Hermann, Sven 
Rieder, Natascha 
Heller, Astrid 

Abstract

Non-invasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer (CRC) xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods: Tumor bearing CD1 nude mice, engrafted with FOLFOX-sensitive Colo205 CRC xenografts, were treated with FOLFOX (5 fluorouracil, leucovorin and oxaliplatin) in weekly intervals. On d1, d2, d6, d9 and d13 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 d1 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), which was accompanied by increases in markers for proliferation (Ki67, TK1) and for activated DNA damage response (DDR; γH2AX), whereas the effect on cell death was minimal. As tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrate that [18F]FLT PET can non-invasively monitor molecular alterations induced by a cancer treatment, including thymidine metabolism and DDR. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements.

Description

Keywords

Animal Imaging, DW-MRI, Oncology: GI, PET, [<sup>18</sup>F]FLT, combination cancer therapy, small animal imaging

Journal Title

Journal of Nuclear Medicine

Conference Name

Journal ISSN

0161-5505
1535-5667

Volume Title

59

Publisher

Science Press
Sponsorship
European Commission FP7 Collaborative projects (CP) (unknown)