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'-[(18)F]fluorothymidine ([(18)F]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 [(3)H]FLT uptake, nucleoside transport, thymidine kinase 1 (TK1) expression and TK1 activity. Static and 2-h dynamic [(18)F]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 [(3)H]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 [(18)F]FLT PET in mice bearing HT29 tumours showed accumulation of [(18)F]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 [(18)F]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 [(18)F]FLT uptake. Mechanisms may involve decreased dephosphorylation of [(18)F]FLT phosphate early after TAS-102 administration. Increased TK1 expression and/or nucleoside transporter may be related to increased [(18)F]FLT uptake at a later time. [(18)F]FLT PET has a potential to assess the pharmacodynamics of TAS-102 in cancer patients.
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