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

J Natl Cancer Inst. 2003 May 7;95(9):675-82. doi: 10.1093/jnci/95.9.675.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Antimetabolites, Antineoplastic / pharmacology*
  • Antimetabolites, Antineoplastic / therapeutic use
  • Area Under Curve
  • Carbon Radioisotopes
  • Case-Control Studies
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Gastrointestinal Neoplasms / diagnostic imaging*
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / enzymology
  • Humans
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Middle Aged
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Regression Analysis
  • Thymidine
  • Thymidylate Synthase / antagonists & inhibitors*
  • Tomography, Emission-Computed* / methods


  • Antimetabolites, Antineoplastic
  • Carbon Radioisotopes
  • Enzyme Inhibitors
  • Quinazolines
  • Thymidylate Synthase
  • nolatrexed
  • Thymidine