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

P Wells; E Aboagye; R Gunn; S Osman; A Boddy; G Taylor; I Rafi; A Hughes; A Calvert; PM Price; D Newell

doi:10.1093/jnci/95.9.675

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

P Wells, E Aboagye, R Gunn, S Osman, A Boddy, G Taylor, I Rafi, A Hughes, A Calvert, PM Price, D Newell

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	J Natl Cancer Inst
Volume	95( 9)
DOIs	https://doi.org/10.1093/jnci/95.9.675
Publication status	Published - 7 May 2003

Keywords

Adult
Aged
pharmacokinetics: Antimetabolites, Antineoplastic
Area Under Curve
diagnostic use: Carbon Radioisotopes
Case-Control Studies
pharmacokinetics: Enzyme Inhibitors
Female
drug therapy: Gastrointestinal Neoplasms
Humans
drug effects: Liver
Male
Middle Aged
pharmacokinetics: Quinazolines
Regression Analysis
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
diagnostic use: Thymidine
antagonists & inhibitors: Thymidylate Synthase
methods: Tomography, Emission-Computed

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/jnci/95.9.675

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@article{39161eee26e34d4cbf55662c4743e99e,

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

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.",

keywords = "Adult, Aged, pharmacokinetics: Antimetabolites, Antineoplastic, Area Under Curve, diagnostic use: Carbon Radioisotopes, Case-Control Studies, pharmacokinetics: Enzyme Inhibitors, Female, drug therapy: Gastrointestinal Neoplasms, Humans, drug effects: Liver, Male, Middle Aged, pharmacokinetics: Quinazolines, Regression Analysis, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., diagnostic use: Thymidine, antagonists & inhibitors: Thymidylate Synthase, methods: Tomography, Emission-Computed",

author = "P Wells and E Aboagye and R Gunn and S Osman and A Boddy and G Taylor and I Rafi and A Hughes and A Calvert and PM Price and D Newell",

year = "2003",

month = may,

day = "7",

doi = "10.1093/jnci/95.9.675",

language = "English",

volume = "95( 9)",

journal = "J Natl Cancer Inst",

issn = "1460-2105",

publisher = "Oxford University Press",

}

TY - JOUR

T1 - 2-[11C]thymidine positron emission tomography as an indicator of thymidylate synthase inhibition in patients treated with AG337.

AU - Wells, P

AU - Aboagye, E

AU - Gunn, R

AU - Osman, S

AU - Boddy, A

AU - Taylor, G

AU - Rafi, I

AU - Hughes, A

AU - Calvert, A

AU - Price, PM

AU - Newell, D

PY - 2003/5/7

Y1 - 2003/5/7

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - pharmacokinetics: Antimetabolites, Antineoplastic

KW - Area Under Curve

KW - diagnostic use: Carbon Radioisotopes

KW - Case-Control Studies

KW - pharmacokinetics: Enzyme Inhibitors

KW - Female

KW - drug therapy: Gastrointestinal Neoplasms

KW - Humans

KW - drug effects: Liver

KW - Male

KW - Middle Aged

KW - pharmacokinetics: Quinazolines

KW - Regression Analysis

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, P.H.S.

KW - diagnostic use: Thymidine

KW - antagonists & inhibitors: Thymidylate Synthase

KW - methods: Tomography, Emission-Computed

U2 - 10.1093/jnci/95.9.675

DO - 10.1093/jnci/95.9.675

M3 - Article

SN - 1460-2105

VL - 95( 9)

JO - J Natl Cancer Inst

JF - J Natl Cancer Inst

ER -

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

Abstract

Keywords

UN SDGs

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