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- Title
Evaluation of [<sup>18</sup>F]Fluorothymidine as a Biomarker for Early Therapy Response in a Mouse Model of Colorectal Cancer.
- Authors
Rapic, Sara; Vangestel, Christel; Verhaeghe, Jeroen; Thomae, David; Pauwels, Patrick; Wyngaert, Tim; Staelens, Steven; Stroobants, Sigrid; Van den Wyngaert, Tim
- Abstract
<bold>Purpose: </bold>In oncology, positron emission tomography imaging using dedicated tracers as biomarkers may assist in early evaluation of therapy efficacy. Using 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), we investigated the early effects of chemotherapeutic treatment on cancer cell proliferation in a BRAF-mutated colorectal cancer xenograft model.<bold>Procedures: </bold>Colo205 subcutaneously inoculated animals underwent 90-min dynamic imaging before and 24 h after treatment with vehicle (control), cetuximab (resistant) or irinotecan (sensitive). Total distribution volume was quantified from dynamic data, and standardized uptake values as well as tumor-to-blood ratios were calculated from static images averaged over the last 20 min. In vivo imaging data was correlated with ex vivo proliferation and thymidine metabolism proteins.<bold>Results: </bold>All imaging parameters showed a significant post-treatment decrease from [18F]FLT baseline uptake for the irinotecan group (p ≤ 0.001) as compared with the cetuximab and vehicle group and correlated strongly with each other (p ≤ 0.0001). In vivo data were in agreement with Ki67 staining, showing a significantly lower percentage of Ki67-positive cells in the irinotecan group as compared with other groups (p ≤ 0.0001). Tumor expression of thymidine kinase 1 phosphorylated on serine 13, thymidylate synthase, and thymidine phosphorylase remained unaffected, while thymidine kinase 1 expression was, surprisingly, significantly higher in irinotecan-treated animals (p ≤ 0.01). In contrast, tumor ATP levels were lowest in this group.<bold>Conclusions: </bold>[18F]FLT positron emission tomography was found to be a suitable biomarker of early tumor response to anti-proliferative treatment, with static imaging not being inferior to full compartmental analysis in our xenograft model. The dynamics of thymidine kinase 1 protein expression and protein activity in low ATP environments merits further investigation.
- Subjects
THYMIDINE; POSITRON emission tomography; COLON cancer treatment; CANCER cell growth; BIOMARKERS; MICE; ADENOSINE triphosphate metabolism; ANIMAL experimentation; BIOLOGICAL models; CELL lines; COLON tumors; DYNAMICS; IMMUNOHISTOCHEMISTRY; RECTUM tumors; RESEARCH evaluation; TRANSFERASES; DEOXYRIBONUCLEOSIDES
- Publication
Molecular Imaging & Biology, 2017, Vol 19, Issue 1, p109
- ISSN
1536-1632
- Publication type
journal article
- DOI
10.1007/s11307-016-0974-5