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

Wells, P; Aboagye, E; Gunn, RN; Osman, S; Boddy, AV; Taylor, GA; Rafi, I; ... Newell, DR; + view all (2003) 2-[C-11]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337. J NATL CANCER I , 95 (9) 675 - 682.

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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-[C-11]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-[C-11]Thymidine PET can be used to measure thymidine salvage kinetics directly in the tissue of interest.

Type: Article
Title: 2-[C-11]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337
Keywords: PROLIFERATION IN-VIVO, NOLATREXED DIHYDROCHLORIDE, PHASE-I, CELLULAR PHARMACOLOGY, GROWTH-INHIBITION, SPECTRAL-ANALYSIS, THERAPY RESPONSE, LIVER METASTASES, ANTICANCER DRUGS, KINETIC-ANALYSIS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/351935
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