Metabolism of 3′-deoxy-3′-[F-18]fluorothymidine in proliferating A549 cells: Validations for positron emission tomography

John R. Grierson, Jeffery L. Schwartz, Mark Muzi, Robert Jordan, Kenneth A. Krohn

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

3′-Deoxy-3′-[F-18]fluorothymidine (FLT) is under clinical evaluation as a metabolic probe for imaging cell proliferation in vivo using positron emission tomography (PET). As part of our validation effort, we followed the short-term metabolism of FLT in exponentially growing tumor cells to demonstrate the enzyme activities within the DNA salvage pathway that influence retention of radioactivity. In A549 cells, thymidine kinase-1 (TK1) activity produced FLTMP, which dominated the labeled nucleotide pool. Subsequent nucleotide phosphorylations by thymidylate kinase (TMPK) and nucleotide diphosphate kinase (NDPK) led to FLTTP. After 1h, the cellular metabolic pool contained ∼30% FLTTP. A putative deoxynucleotidase (dNT), which degrades FLTMP to FLT, provided the primary mechanism for tracer efflux from cells. In contrast, FLTTP was resistant to degradation and highly retained. The uptake and retention characteristics of FLT were also compared to those of thymidine, FMAU (2′-arabino-fluoro-TdR) and FIAU (2′-arabino-fluoro-5-iodo- 2′-dexoyuridine). Despite the fact that FLT lacks the 3′-hydroxy necessary for its incorporation into DNA it out performed both FMAU and FIAU in terms of uptake and retention.

Original languageEnglish (US)
Pages (from-to)829-837
Number of pages9
JournalNuclear Medicine and Biology
Volume31
Issue number7
DOIs
StatePublished - Oct 1 2004

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Keywords

  • DNA salvage pathway
  • FLT
  • Fluorothymidine
  • Nucleoside metabolism
  • PET

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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