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 Krohn

Research output: Contribution to journalArticle

107 Citations (Scopus)

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 2003
Externally publishedYes

Fingerprint

Thymidine
Cell Proliferation
Cell Line
S Phase
DNA
Neoplasms
Cell Cycle Checkpoints
Growth
Uracil
Tumor Cell Line
Nucleosides
Nucleotides
Phosphorylation
Enzymes
thymidine kinase 1
Clevudine

Keywords

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

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. / Schwartz, Jeffrey L.; Tamura, Yasuko; Jordan, Robert; Grierson, John R.; Krohn, Kenneth.

In: Journal of Nuclear Medicine, Vol. 44, No. 12, 12.2003, p. 2027-2032.

Research output: Contribution to journalArticle

Schwartz, Jeffrey L. ; Tamura, Yasuko ; Jordan, Robert ; Grierson, John R. ; Krohn, Kenneth. / Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. In: Journal of Nuclear Medicine. 2003 ; Vol. 44, No. 12. pp. 2027-2032.
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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.",
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N2 - 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.

AB - 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.

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