2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337.
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.
Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Paula
P
Wells
Eric
E
Aboagye
Roger N
RN
Gunn
Safiye
S
Osman
Alan V
AV
Boddy
Gordon A
GA
Taylor
Imran
I
Rafi
Andrew N
AN
Hughes
A Hilary
AH
Calvert
Pat M
PM
Price
David R
DR
Newell
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D002250:Carbon Radioisotopes; D016022:Case-Control Studies; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012044:Regression Analysis; D013936:Thymidine; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014055:Tomography, Emission-Computed / Q000379:methods
D000964:Antimetabolites, Antineoplastic; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D011799:Quinazolines; D013940:Thymidylate Synthase; C099178:nolatrexed; D013936:Thymidine