Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs

Jeffrey L. Schwartz, Yasuko Tamura, Robert Jordan, John R. Grierson, Kenneth A. Krohn

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

The use of radiolabeled thymidine (TdR) and thymidine analogs as PET-based tracers of tumor growth rate is based on the assumption that measurement of uptake of these nucleosides, a function primarily of thymidine kinase-1 (TK 1) activity, provides an accurate measure of active cell proliferation in tumors. The goal of this study was to test this hypothesis and determine how well these tracers track changes in proliferation of tumor cells. Methods: TK1 activity; S-phase fraction; and uptake of TdR, 3′-deoxy-3′-fluorothymidine (FLT), and 2′-fluoro-5-methyl-1- (β-D-2-arabino-furanosyl) uracil (FMAU) were determined in plateau-phase and exponentially growing cultures of 3 human and 3 murine tumor cell lines. Results: TK1 activity and S-phase fraction increased in all cell lines as cells moved from plateau-phase conditions to exponential growth. Some cell lines had relatively large TK1 activities and S-phase fractions under plateau-phase conditions, consistent with a loss of normal cell cycle checkpoint control in these cells. There were also 2 cell lines in which TK 1 activity changed little as cells moved from the plateau phase to exponential growth, suggesting that in these cell lines, de novo nucleotide synthesis pathways predominate over salvage pathways. Both TdR and FLT detected changes in TK1 activity. The slope of the relationship between TdR uptake and TK1 activity was nearly twice that for FLT and more than 40-fold that for FMAU. Conclusion: Although not all tumors show a strong TK 1 dependence of proliferation, in all cell lines for which proliferation is highly TK1 dependent, phosphorylation of TdR or FLT accurately reflects changes in TK1 enzyme activity.

Original languageEnglish (US)
Pages (from-to)2027-2032
Number of pages6
JournalJournal of Nuclear Medicine
Volume44
Issue number12
StatePublished - Dec 1 2003

    Fingerprint

Keywords

  • 2′-fluoro-5-methyl-1-(β- d-2-arabino-furanosyl) uracil
  • 3′-deoxy-3′-fluorothymidine
  • Cell proliferation
  • Thymidine kinase

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this