title: In vitro analysis of transport and metabolism of 4'-thiothymidine in human tumor cells.
abstract: BACKGROUND
  The use of thymidine (TdR) and thymidine analogs such as 3'-fluoro-3'-deoxythymidine (FLT) as positron emission tomography (PET)-based proliferation markers can provide information on tumor response to treatment. Studies on another TdR analog, 4'-thiothymidine (4DST), suggest that it might be a better PET-based proliferation tracer than either TdR or FLT. 4DST is resistant to the catabolism that complicates analysis of TdR in PET studies, but unlike FLT, 4DST is incorporated into DNA.
  
  
  METHODS
  To further evaluate 4DST, the kinetics of 4DST transport and metabolism were determined and compared to FLT and TdR. Transport and metabolism of FLT, TdR and 4DST were examined in the human adenocarcinoma cell line A549 under exponential-growth conditions. Single cell suspensions were incubated in buffer supplemented with radiolabeled tracer in the presence or absence of nitrobenzylmercaptopurine ribonucleoside (NBMPR), an inhibitor of equilibrative nucleoside transporters (ENT). Kinetics of tracer uptake was determined in whole cells and tracer metabolism measured by high performance liquid chromatography of cell lysates.
  
  
  RESULTS
  TdR and 4DST were qualitatively similar in terms of ENT-dependent transport, shapes of uptake curves, and relative levels of DNA incorporation. FLT did not incorporate into DNA, showed a significant temperature effect for uptake, and its transport had a significant NBMPR-resistant component. Overall 4DST metabolism was significantly slower than either TdR or FLT.
  
  
  CONCLUSIONS
  4DST provides a good alternative for TdR in PET and has advantages over FLT in proliferation measurement. However, slow 4DST metabolism and the short half-life of the (11)C label might limit widespread use in PET.
authors: Department of Radiation Oncology, University of Washington, Seattle, WA.
authors: David A
authors: DA
authors: Plotnik
authors: Department of Radiation Oncology, University of Washington, Seattle, WA.
authors: Stephen
authors: S
authors: Wu
authors: Department of Radiation Oncology, University of Washington, Seattle, WA.
authors: Geoffrey R
authors: GR
authors: Linn
authors: Department of Radiation Oncology, University of Washington, Seattle, WA.
authors: Franco Chi Tat
authors: FCT
authors: Yip
authors: Department of Radiation Oncology, University of Washington, Seattle, WA.
authors: Natacha Lou
authors: NL
authors: Comandante
authors: Department of Radiation Oncology, University of Washington, Seattle, WA; Department of Radiology, University of Washington, Seattle, WA.
authors: Kenneth A
authors: KA
authors: Krohn
authors: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors: Jun
authors: J
authors: Toyohara
authors: Department of Radiation Oncology, University of Washington, Seattle, WA. Electronic address: jschwart@uw.edu.
authors: Jeffrey L
authors: JL
authors: Schwartz
mesh_terms: D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D049268:Positron-Emission Tomography; D013872:Thionucleosides / Q000378:metabolism*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D013872:Thionucleosides; C070456:4'-thiothymidine; D013936:Thymidine
keywords: 4′-[methyl-(11)C]thiothymidine; FLT; Nucleoside metabolism; PET imaging