title: 18F-FLT and 125I-IdUrd uptake increase in human tumour cell lines induced by the thymidylate synthase inhibitor FdUrd.
abstract: OBJECTIVE
  5-fluoro-2'-deoxyuridine (FdUrd) depletes the endogenous 5'-deoxythymidine triphosphate (dTTP) pool. We hypothesized whether uptake of exogenous dThd analogues could be favoured through a feedback enhanced salvage pathway and studied the FdUrd effect on cellular uptake of 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) and 5-125I-iodo-2'-deoxyuridine (125I-IdUrd) in different cancer cell lines in parallel.
  
  
  METHODS
  Cell uptake of 18F-FLT and 125I-IdUrd was studied in 2 human breast, 2 colon cancer and 2 glioblastoma lines. Cells were incubated with/without 1 µmol/l FdUrd for 1 h and, after washing, with 1.2 MBq 18F-FLT or 125I-IdUrd for 0.3 to 2 h. Cell bound 18F-FLT and 125I-IdUrd was counted and expressed in % incubated activity (%IA). Kinetics of 18F-FLT cell uptake and release were studied with/without FdUrd modulation. 2'-3H-methyl-fluorothymidine (2'-3H-FLT) uptake with/without FdUrd pretreatment was tested on U87 spheroids and monolayer cells.
  
  
  RESULTS
  Basal uptake at 2 h of 18F-FLT and 125I-IdUrd was in the range of 0.8-1.0 and 0.4-0.6 Bq/cell, respectively. FdUrd pretreatment enhanced 18F-FLT and 125I-IdUrd uptake 1.2-2.1 and 1.7-4.4 fold, respectively, while co-incubation with excess thymidine abrogated all 18F-FLT uptake. FdUrd enhanced 18F-FLT cellular inflow in 2 breast cancer lines by factors of 1.8 and 1.6, respectively, while outflow persisted at a slightly lower rate. 2'-3H-FLT basal uptake was very low while uptake increase after FdUrd was similar in U87 monolayer cells and spheroids.
  
  
  CONCLUSIONS
  Basal uptake of 18F-FLT was frequently higher than that of 125I-IdUrd but FdUrd induced uptake enhancement was stronger for 125I-IdUrd in five of six cell lines. 18F-FLT outflow from cells might be an explanation for the observed difference with 125I-IdUrd.
authors.affiliation: Department of Nuclear Medicine, University Hospital of Lausanne, Switzerland. Franz.Buchegger@chuv.ch
authors.forename: D
authors.initials: D
authors.lastname: Viertl
authors.forename: F
authors.initials: F
authors.lastname: Perillo-Adamer
authors.forename: P-A
authors.initials: PA
authors.lastname: André
authors.forename: S M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: T L
authors.initials: TL
authors.lastname: Ross
authors.forename: M
authors.initials: M
authors.lastname: Kosinski
authors.forename: Y M
authors.initials: YM
authors.lastname: Dupertuis
authors.forename: A
authors.initials: A
authors.lastname: Bischof Delaloye
authors.forename: F
authors.initials: F
authors.lastname: Buchegger
mesh_terms: D045744:Cell Line, Tumor / Q000000981:diagnostic imaging / Q000378:metabolism*; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D005467:Floxuridine / Q000008:administration & dosage*; D006801:Humans; D007065:Idoxuridine / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics
chemical_list: D015224:Dideoxynucleosides; D019275:Radiopharmaceuticals; D005467:Floxuridine; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D007065:Idoxuridine; C002854:alovudine