title: Positron emission tomography imaging of human colon cancer xenografts in mice with [18F]fluorothymidine after TAS-102 treatment.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea.
authors.forename: Haeng Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Oh
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.forename: Jin Hwa
authors.initials: JH
authors.lastname: Chung
authors.forename: Yeseulmi
authors.initials: Y
authors.lastname: Kim
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Ryu
authors.forename: Seog Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Dae Hyuk
authors.initials: DH
authors.lastname: Moon
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D015224:Dideoxynucleosides / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D005462:Fluorine Radioisotopes; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D011759:Pyrrolidines; D019275:Radiopharmaceuticals / Q000494:pharmacology; D011897:Random Allocation; D013937:Thymidine Kinase / Q000378:metabolism; D013941:Thymine; D014271:Trifluridine / Q000494:pharmacology*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; D005462:Fluorine Radioisotopes; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C002854:alovudine; D013941:Thymine; D014271:Trifluridine