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

Lookup NU author(s): Professor Alan Boddy, Gordon Taylor, Dr Andrew Hughes, Professor Alan Calvert, Professor Herbie Newell

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Abstract

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 metadata

Author(s): Wells, P., Aboagye, E., Gunn, R., Osman, S., Boddy, A. V., Taylor, G. A., Rafi, I., Hughes, A. N., Calvert, A. H., Price, P., Newell, D. R.

Publication type: Article

Publication status: Published

Journal: Journal of the National Cancer Institute

Year: 2003

Volume: 95

Issue: 9

Pages: 675-682

Print publication date: 07/05/2003

ISSN (print): 0027-8874

ISSN (electronic): 1460-2105

URL: http://dx.doi.org/10.1093/jnci/95.9.675

DOI: 10.1093/jnci/95.9.675

PubMed id: 12734319

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