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01-05-2015 | Original Article

Positron emission tomography imaging of human colon cancer xenografts in mice with [¹⁸F]fluorothymidine after TAS-102 treatment

Authors: Haeng Jung Lee, Seung Jun Oh, Eun Jung Lee, Jin Hwa Chung, Yeseulmi Kim, Jin-Sook Ryu, Seog Young Kim, Seung Jin Lee, Dae Hyuk Moon, Tae Won Kim

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2015

Abstract

Purpose

TAS-102 is an orally administered anticancer agent composed of α,α,α-trifluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI). This study assessed 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) uptake after TAS-102 administration.

Methods

The human colorectal carcinoma cell lines HCT116, HT29, HCT8 and SW620 were exposed to FTD for 2 h, further incubated for 0, 2 and 24 h, and assayed for [³H]FLT uptake, nucleoside transport, thymidine kinase 1 (TK1) expression and TK1 activity. Static and 2-h dynamic [¹⁸F]FLT positron emission tomography (PET) was performed in mice bearing HT29 or SW620 tumours orally administered with vehicle or TAS-102.

Results

FTD decreased the viability of all cell lines, whereas increased [³H]FLT uptake (P < 0.05). Increased nucleoside transport and/or TK1 expression were observed 24 h after FTD, but not in 0–2 h. Static [¹⁸F]FLT PET in mice bearing HT29 tumours showed accumulation of [¹⁸F]FLT in tumours 1 h (day 1) after TAS-102. Two-hour dynamic PET in mice bearing SW620 tumours showed increased influx constant and volume of distribution of phosphorylated [¹⁸F]FLT on days 1 and 8 (P < 0.05) after TAS-102 with decreased dephosphorylation on day 1 (P < 0.001). Ex vivo studies showed that SW620 tumours after TAS-102 had higher TK1 expression than those with vehicle on days 8 and 15.

Conclusion

TAS-102 administration induces an increase in [¹⁸F]FLT uptake. Mechanisms may involve decreased dephosphorylation of [¹⁸F]FLT phosphate early after TAS-102 administration. Increased TK1 expression and/or nucleoside transporter may be related to increased [¹⁸F]FLT uptake at a later time. [¹⁸F]FLT PET has a potential to assess the pharmacodynamics of TAS-102 in cancer patients.

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Title: Positron emission tomography imaging of human colon cancer xenografts in mice with [18F]fluorothymidine after TAS-102 treatment
Authors: Haeng Jung Lee
Seung Jun Oh
Eun Jung Lee
Jin Hwa Chung
Yeseulmi Kim
Jin-Sook Ryu
Seog Young Kim
Seung Jin Lee
Dae Hyuk Moon
Tae Won Kim
Publication date: 01-05-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2015
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2718-7

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