2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337.

P Wells, E Aboagye, R Gunn, S Osman, A Boddy, G Taylor, I Rafi, A Hughes, A Calvert, PM Price, D Newell

    Research output: Contribution to journalArticlepeer-review


    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.
    Original languageEnglish
    JournalJ Natl Cancer Inst
    Volume95( 9)
    Publication statusPublished - 7 May 2003


    • Adult
    • Aged
    • pharmacokinetics: Antimetabolites, Antineoplastic
    • Area Under Curve
    • diagnostic use: Carbon Radioisotopes
    • Case-Control Studies
    • pharmacokinetics: Enzyme Inhibitors
    • Female
    • drug therapy: Gastrointestinal Neoplasms
    • Humans
    • drug effects: Liver
    • Male
    • Middle Aged
    • pharmacokinetics: Quinazolines
    • Regression Analysis
    • Research Support, Non-U.S. Gov't
    • Research Support, U.S. Gov't, P.H.S.
    • diagnostic use: Thymidine
    • antagonists & inhibitors: Thymidylate Synthase
    • methods: Tomography, Emission-Computed


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