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

2.50
Hdl Handle:
http://hdl.handle.net/10541/78179
Title:
2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337.
Authors:
Wells, Paula; Aboagye, E O; Gunn, Roger N; Osman, Saifa; Boddy, Alan V; Taylor, Gordon A; Rafi, Imran; Hughes, Andrew; Calvert, A Hilary; Price, Patricia M; Newell, David R
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.
Affiliation:
Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Citation:
2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337. 2003, 95 (9):675-82 J. Natl. Cancer Inst.
Journal:
Journal of the National Cancer Institute
Issue Date:
7-May-2003
URI:
http://hdl.handle.net/10541/78179
PubMed ID:
12734319
Type:
Article
Language:
en
ISSN:
1460-2105
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorWells, Paula-
dc.contributor.authorAboagye, E O-
dc.contributor.authorGunn, Roger N-
dc.contributor.authorOsman, Saifa-
dc.contributor.authorBoddy, Alan V-
dc.contributor.authorTaylor, Gordon A-
dc.contributor.authorRafi, Imran-
dc.contributor.authorHughes, Andrew-
dc.contributor.authorCalvert, A Hilary-
dc.contributor.authorPrice, Patricia M-
dc.contributor.authorNewell, David R-
dc.date.accessioned2009-08-21T12:00:06Z-
dc.date.available2009-08-21T12:00:06Z-
dc.date.issued2003-05-07-
dc.identifier.citation2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337. 2003, 95 (9):675-82 J. Natl. Cancer Inst.en
dc.identifier.issn1460-2105-
dc.identifier.pmid12734319-
dc.identifier.urihttp://hdl.handle.net/10541/78179-
dc.description.abstractBACKGROUND: 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.en
dc.language.isoenen
dc.subjectGastrointestinal Canceren
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAntimetabolites, Antineoplastic-
dc.subject.meshArea Under Curve-
dc.subject.meshCarbon Radioisotopes-
dc.subject.meshCase-Control Studies-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshFemale-
dc.subject.meshGastrointestinal Neoplasms-
dc.subject.meshHumans-
dc.subject.meshLiver-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshQuinazolines-
dc.subject.meshRegression Analysis-
dc.subject.meshThymidine-
dc.subject.meshThymidylate Synthase-
dc.subject.meshTomography, Emission-Computed-
dc.title2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337.en
dc.typeArticleen
dc.contributor.departmentImperial College School of Medicine, Hammersmith Hospital, London, UK.en
dc.identifier.journalJournal of the National Cancer Instituteen

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