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 language | English (US) |
|---|---|
| Pages (from-to) | 2027-2032 |
| Number of pages | 6 |
| Journal | Journal of Nuclear Medicine |
| Volume | 44 |
| Issue number | 12 |
| State | Published - Dec 2003 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs
AU - Schwartz, Jeffrey L.
AU - Tamura, Yasuko
AU - Jordan, Robert
AU - Grierson, John R.
AU - Krohn, Kenneth
PY - 2003/12
Y1 - 2003/12
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.
KW - 2′-fluoro-5-methyl-1-(β- d-2-arabino-furanosyl) uracil
KW - 3′-deoxy-3′-fluorothymidine
KW - Cell proliferation
KW - Thymidine kinase
UR - http://www.scopus.com/inward/record.url?scp=1542681635&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1542681635&partnerID=8YFLogxK
M3 - Article
C2 - 14660729
AN - SCOPUS:1542681635
VL - 44
SP - 2027
EP - 2032
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
SN - 0161-5505
IS - 12
ER -