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

TAS-102 is an orally administered anticancer agent composed of alpha,alpha,alpha-trifluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI). This study assessed 3'-deoxy-3'-[F-18]fluorothymidine ([F-18]FLT) uptake after TAS-102 administration. 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 [H-3]FLT uptake, nucleoside transport, thymidine kinase 1 (TK1) expression and TK1 activity. Static and 2-h dynamic [F-18]FLT positron emission tomography (PET) was performed in mice bearing HT29 or SW620 tumours orally administered with vehicle or TAS-102. FTD decreased the viability of all cell lines, whereas increased [H-3]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 [F-18]FLT PET in mice bearing HT29 tumours showed accumulation of [F-18]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 [F-18]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. TAS-102 administration induces an increase in [F-18]FLT uptake. Mechanisms may involve decreased dephosphorylation of [F-18]FLT phosphate early after TAS-102 administration. Increased TK1 expression and/or nucleoside transporter may be related to increased [F-18]FLT uptake at a later time. [F-18]FLT PET has a potential to assess the pharmacodynamics of TAS-102 in cancer patients.