HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mankoff, D. A. Articles by Krohn, K. A. Search for Related Content PubMed PubMed Citation Articles by Mankoff, D. A. Articles by Krohn, K. A.

Kinetic Analysis of 2-[¹¹C]Thymidine PET Imaging Studies: Validation Studies

Division of Nuclear Medicine, University of Washington, Seattle, Washington
Wayne State University and the Karmanos Cancer Institute, Detroit, Michigan

Correspondence: For correspondence or reprints contact: David A. Mankoff, MD, PhD, Division of Nuclear Medicine, Box 356113, University of Washington Medical Center, 1959 NE Pacific St., Seattle, WA 98195.

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.

Key Words: PET • thymidine • kinetic modeling • cancer

This article has been cited by other articles:

				R. Ullrich, H. Backes, H. Li, L. Kracht, H. Miletic, K. Kesper, B. Neumaier, W.-D. Heiss, K. Wienhard, and A. H. Jacobs Glioma Proliferation as Assessed by 3'-Fluoro-3'-Deoxy-L-Thymidine Positron Emission Tomography in Patients with Newly Diagnosed High-Grade Glioma Clin. Cancer Res., April 1, 2008; 14(7): 2049 - 2055. [Abstract] [Full Text] [PDF]

				S. Nimmagadda, T. J. Mangner, H. Sun, R. W. Klecker Jr., O. Muzik, J. M. Lawhorn-Crews, K. A. Douglas, J. M. Collins, and A. F. Shields Biodistribution and Radiation Dosimetry Estimates of 1-(2'-Deoxy-2'-18F-Fluoro-1-{beta}-D-Arabinofuranosyl)-5-Bromouracil: PET Imaging Studies in Dogs J. Nucl. Med., November 1, 2005; 46(11): 1916 - 1922. [Abstract] [Full Text] [PDF]

				M. Muzi, D. A. Mankoff, J. R. Grierson, J. M. Wells, H. Vesselle, and K. A. Krohn Kinetic Modeling of 3'-Deoxy-3'-Fluorothymidine in Somatic Tumors: Mathematical Studies J. Nucl. Med., February 1, 2005; 46(2): 371 - 380. [Abstract] [Full Text] [PDF]

				A. van Waarde, D. C.P. Cobben, A. J.H. Suurmeijer, B. Maas, W. Vaalburg, E. F.J. de Vries, P. L. Jager, H. J. Hoekstra, and P. H. Elsinga Selectivity of 18F-FLT and 18F-FDG for Differentiating Tumor from Inflammation in a Rodent Model J. Nucl. Med., April 1, 2004; 45(4): 695 - 700. [Abstract] [Full Text] [PDF]

				J. L. Schwartz, Y. Tamura, R. Jordan, J. R. Grierson, and K. A. Krohn Monitoring Tumor Cell Proliferation by Targeting DNA Synthetic Processes with Thymidine and Thymidine Analogs J. Nucl. Med., December 1, 2003; 44(12): 2027 - 2032. [Abstract] [Full Text] [PDF]

				M. Wagner, U. Seitz, A. Buck, B. Neumaier, S. Schultheiss, M. Bangerter, M. Bommer, F. Leithauser, E. Wawra, G. Munzert, et al. 3'-[18F]Fluoro-3'-Deoxythymidine ([18F]-FLT) as Positron Emission Tomography Tracer for Imaging Proliferation in a Murine B-Cell Lymphoma Model and in the Human Disease Cancer Res., May 15, 2003; 63(10): 2681 - 2687. [Abstract] [Full Text] [PDF]

				P. Wells, E. Aboagye, R. N. Gunn, S. Osman, A. V. Boddy, G. A. Taylor, I. Rafi, A. N. Hughes, A. H. Calvert, P. M. Price, et al. 2-[11C]Thymidine Positron Emission Tomography as an Indicator of Thymidylate Synthase Inhibition in Patients Treated With AG337 J Natl Cancer Inst, May 7, 2003; 95(9): 675 - 682. [Abstract] [Full Text] [PDF]

				H. Vesselle, J. Grierson, M. Muzi, J. M. Pugsley, R. A. Schmidt, P. Rabinowitz, L. M. Peterson, E. Vallieres, and D. E. Wood In Vivo Validation of 3'deoxy-3'-[18F]fluorothymidine ([18F]FLT) as a Proliferation Imaging Tracer in Humans: Correlation of [18F]FLT Uptake by Positron Emission Tomography with Ki-67 Immunohistochemistry and Flow Cytometry in Human Lung Tumors Clin. Cancer Res., November 1, 2002; 8(11): 3315 - 3323. [Abstract] [Full Text] [PDF]

				J. S. Rasey, J. R. Grierson, L. W. Wiens, P. D. Kolb, and J. L. Schwartz Validation of FLT Uptake as a Measure of Thymidine Kinase-1 Activity in A549 Carcinoma Cells J. Nucl. Med., September 1, 2002; 43(9): 1210 - 1217. [Abstract] [Full Text] [PDF]

				J. R. Bading, M. M. Alauddin, J. D. Fissekis, A. H. Shahinian, J. Joung, T. Spector, and P. S. Conti Blocking Catabolism with Eniluracil Enhances PET Studies of 5-[18F]Fluorouracil Pharmacokinetics J. Nucl. Med., October 1, 2000; 41(10): 1714 - 1724. [Abstract] [Full Text] [PDF]