2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337.
2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337.
复制标题
2-[11C]胸苷正电子发射断层扫描作为接受 AG337 治疗的患者胸苷酸合成酶抑制的指标。
DOI：
10.1093/jnci/95.9.675
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Newell,DavidR
中科院分区：
文献类型：
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作者：
Wells,Paula;Aboagye,Eric;Gunn,RogerN;Osman,Safiye;Boddy,AlanV;Taylor,GordonA;Rafi,Imran;Hughes,AndrewN;Calvert,AHilary;Price,PatM;Newell,DavidR
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 kineticsin vivoin 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 measuredin vivousing 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–WhitneyUtest. 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.
