© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 9, 675-682,
May 7, 2003
© 2003 Oxford University Press
ARTICLE |
2-[11C]Thymidine Positron Emission Tomography as an Indicator of Thymidylate Synthase Inhibition in Patients Treated With AG337
Affiliations of authors: P. Wells, E. Aboagye, R. N. Gunn, S. Osman, P. M. Price, Imperial College School of Medicine, Hammersmith Hospital, London, U.K.; A. V. Boddy, G. A. Taylor, I. Rafi, A. N. Hughes, A. H. Calvert, D. R. Newell, Northern Institute for Cancer Research, University of Newcastle, Newcastle, U.K.
Correspondence to: Pat Price, M.D., Molecular Imaging Centre, Academic Department of Radiation Oncology, Christie Hospital NHS Trust, Wilmslow Rd., Manchester, M20 4BX, U.K. (e-mail: anne.mason{at}man.ac.uk).
Background: Some anticancer drugs inhibit thymidylate synthase (TS), a key enzyme for thymidine nucleotide biosynthesis. Cells can compensate for depleted thymidine levels by taking up extracellular thymidine via a salvage pathway. We investigated the use of 2-[11C]thymidine positron emission tomography (PET) to measure thymidine salvage kinetics in vivo in humans. Methods: Five patients with advanced gastrointestinal cancer were PET scanned both before and 1 hour after oral administration of the TS inhibitor AG337 (THYMITAQ [nolatrexed]); seven control patients were scanned twice but not treated with AG337. Thymidine salvage kinetics were measured in vivo using 2-[11C]thymidine PET and spectral analysis to obtain the standardized uptake values (SUV), the area under the time–activity curve (AUC), and the fractional retention of thymidine (FRT). Changes in PET parameters between scans in the AG337-treated and control groups were compared using the Mann–Whitney U test. The relationship between AG337 exposure and AG337-induced changes in tumor FRT and in plasma deoxyuridine levels (a conventional pharmacodynamic systemic measure of TS inhibition) was examined using Spearman’s regression analysis. Statistical tests were two-sided. Results: The between-scan change in FRT in patients treated with AG337 (38% increase, 95% confidence interval [CI] = 8% to 68%) was higher than that in control patients (3% increase, 95% CI = –11% to 17%) (P = .028). The level of AG337-induced increase in both 2-[11C]thymidine FRT and plasma deoxyuridine levels was statistically significantly correlated with AG337 exposure (r = 1.00, P = .01 for both). Conclusions: AG337 administration was associated with increased tumor tracer retention that was consistent with tumor cell uptake of exogenous 2-[11C]thymidine as a result of TS inhibition. 2-[11C]Thymidine PET can be used to measure thymidine salvage kinetics directly in the tissue of interest.
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