Kinetic analysis of 2-[11C]thymidine PET imaging studies: Validation studies

David A. Mankoff, Anthony F. Shields, Jeanne Link, Michael M. Graham, Mark Muzi, Lanell M. Peterson, Janet F. Eary, Kenneth Krohn

Research output: Contribution to journalArticle

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Abstract

2-[11C]thymidine has been tested as a PET tracer of cellular proliferation. We have previously described a model of thymidine and labeled metabolite kinetics for use in quantifying the flux of thymidine into DNA as a measure of tumor proliferation. We describe here the results of studies to validate some of the model's assumptions and to test the model's ability to predict the time course of tracer incorporation into DNA in tumors. Methods: Three sets of studies were conducted: (a) The uptake of tracers in proliferative tissues of normal mice was measured early after injection to assess the relative delivery of thymidine and metabolites of thymidine catabolism (thymine and CO2) and calculate relative blood-tissue transfer rates (relative K1s). (b) By using sequential injections of [11C]thymidine and [11C]thymine in normal human volunteers, the kinetics of the first labeled metabolite were measured to determine whether it was trapped in proliferating tissue such as the bone marrow. (c) In a multitumor rat model, 2-[14C]thymidine injection, tumor sampling and quantitative DNA extraction were performed to measure the time course of label uptake into DNA for comparison with model predictions. Results: Studies in mice showed consistent relative delivery of thymidine and metabolites in somatic tissue but, as expected, showed reduced delivery of thymidine and thymine in the normal brain compared to CO2. Thymine studies in volunteers showed only minimal trapping of label in bone marrow in comparison to thymidine. This quantity of trapping could be explained by a small amount of fixation of labeled CO2 in tissue, a process that is included as part of the model. Uptake experiments in rats showed early incorporation of label into DNA, and the model was able to fit the time course of uptake. Conclusion: These initial studies support the assumptions of the compartmental model and demonstrate its ability to quantify thymidine flux into DNA by using 2-[11C]thymidine and PET. Results suggest that further work will be necessary to investigate the effects of tumor heterogeneity and to compare PET measures of tumor proliferation to in vitro measures of proliferation and to clinical tumor behavior in patients undergoing therapy.

Original languageEnglish (US)
Pages (from-to)614-624
Number of pages11
JournalJournal of Nuclear Medicine
Volume40
Issue number4
StatePublished - Apr 1999
Externally publishedYes

Fingerprint

Validation Studies
Thymidine
Thymine
DNA
Neoplasms
Injections
Bone Marrow
Aptitude
Volunteers
Healthy Volunteers
Cell Proliferation

Keywords

  • Cancer
  • Kinetic modeling
  • PET
  • Thymidine

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Mankoff, D. A., Shields, A. F., Link, J., Graham, M. M., Muzi, M., Peterson, L. M., ... Krohn, K. (1999). Kinetic analysis of 2-[11C]thymidine PET imaging studies: Validation studies. Journal of Nuclear Medicine, 40(4), 614-624.

Kinetic analysis of 2-[11C]thymidine PET imaging studies : Validation studies. / Mankoff, David A.; Shields, Anthony F.; Link, Jeanne; Graham, Michael M.; Muzi, Mark; Peterson, Lanell M.; Eary, Janet F.; Krohn, Kenneth.

In: Journal of Nuclear Medicine, Vol. 40, No. 4, 04.1999, p. 614-624.

Research output: Contribution to journalArticle

Mankoff, DA, Shields, AF, Link, J, Graham, MM, Muzi, M, Peterson, LM, Eary, JF & Krohn, K 1999, 'Kinetic analysis of 2-[11C]thymidine PET imaging studies: Validation studies', Journal of Nuclear Medicine, vol. 40, no. 4, pp. 614-624.
Mankoff DA, Shields AF, Link J, Graham MM, Muzi M, Peterson LM et al. Kinetic analysis of 2-[11C]thymidine PET imaging studies: Validation studies. Journal of Nuclear Medicine. 1999 Apr;40(4):614-624.
Mankoff, David A. ; Shields, Anthony F. ; Link, Jeanne ; Graham, Michael M. ; Muzi, Mark ; Peterson, Lanell M. ; Eary, Janet F. ; Krohn, Kenneth. / Kinetic analysis of 2-[11C]thymidine PET imaging studies : Validation studies. In: Journal of Nuclear Medicine. 1999 ; Vol. 40, No. 4. pp. 614-624.
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abstract = "2-[11C]thymidine has been tested as a PET tracer of cellular proliferation. We have previously described a model of thymidine and labeled metabolite kinetics for use in quantifying the flux of thymidine into DNA as a measure of tumor proliferation. We describe here the results of studies to validate some of the model's assumptions and to test the model's ability to predict the time course of tracer incorporation into DNA in tumors. Methods: Three sets of studies were conducted: (a) The uptake of tracers in proliferative tissues of normal mice was measured early after injection to assess the relative delivery of thymidine and metabolites of thymidine catabolism (thymine and CO2) and calculate relative blood-tissue transfer rates (relative K1s). (b) By using sequential injections of [11C]thymidine and [11C]thymine in normal human volunteers, the kinetics of the first labeled metabolite were measured to determine whether it was trapped in proliferating tissue such as the bone marrow. (c) In a multitumor rat model, 2-[14C]thymidine injection, tumor sampling and quantitative DNA extraction were performed to measure the time course of label uptake into DNA for comparison with model predictions. Results: Studies in mice showed consistent relative delivery of thymidine and metabolites in somatic tissue but, as expected, showed reduced delivery of thymidine and thymine in the normal brain compared to CO2. Thymine studies in volunteers showed only minimal trapping of label in bone marrow in comparison to thymidine. This quantity of trapping could be explained by a small amount of fixation of labeled CO2 in tissue, a process that is included as part of the model. Uptake experiments in rats showed early incorporation of label into DNA, and the model was able to fit the time course of uptake. Conclusion: These initial studies support the assumptions of the compartmental model and demonstrate its ability to quantify thymidine flux into DNA by using 2-[11C]thymidine and PET. Results suggest that further work will be necessary to investigate the effects of tumor heterogeneity and to compare PET measures of tumor proliferation to in vitro measures of proliferation and to clinical tumor behavior in patients undergoing therapy.",
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