TY - JOUR
T1 - Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma
T2 - A positron emission tomography study in rats
AU - Bading, James R.
AU - Yoo, Paul B.
AU - Fissekis, John D.
AU - Alauddin, Mian M.
AU - D'Argenio, David Z.
AU - Conti, Peter S.
PY - 2003/7/1
Y1 - 2003/7/1
N2 - Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Positron emission tomography (PET) with 5-[18F]FU (PET/5-[18F]FU) is potentially useful for noninvasive measurement of these processes, but is severely hampered by rapid catabolism of 5-[18F]FU in vivo. This study explored the combined use of PET/5-[18F]FU and eniluracil (5-ethynyluracil), a potent inhibitor of 5-FU catabolism, to measure the pharmacokinetics of 5-FU uptake and metabolism in tumors. Rats bearing a s.c. implanted rat colon tumor were given eniluracil and injected i.v. with 5-[18F]FU. Dynamic PET and arterial blood sampling were performed 0-2 h. Tumors (n = 5) were then rapidly excised, frozen, and analyzed for labeled metabolites by high performance liquid chromatography. Tumor TACs were analyzed by compartmental modeling. Compartments were identified with molecular species by comparison with ex vivo assays. Tumor extracellular fluid volume was determined in a separate group of rats. Kinetic analysis indicated partial trapping of 18F within tumors 0-2 h after injection. Tumor time-activity curves conformed closely to a catenary 3-compartment, 5-parameter model. The model yielded values for 5-FU clearance from plasma into the trap that agreed closely with those reported previously for gastrointestinal tumors from a PET/5-[18F]FU + eniluracil study in humans. Tumor extracellular fluid volume as measured with 99mTc DTPA [(3.1 ± 0.2) × 10-1 ml/g; n = 5] agreed well with the distribution volume for compartment 1 of the 3-compartment, 5-parameter model [(3.7 ± 0.3) × 10-1ml/g; n = 5], thus indicating that compartment 1 corresponds to tumor extracellular space. Compartment 3 closely matched the combined magnitudes of 18F fluoro-nucleoside (FN) triphosphates and macromolecules in all of the cases, and compartment 2 was quantitatively consistent with the sum of intracellular 5-FU, FNs, and FN mono- and diphosphates. These observations show that PET/5-[18F]FU combined with an inhibitor of 5-FU catabolism and compartmental modeling is capable of quantifying the following for 5-FU in tumors: distribution volume in the extracellular space, cell transport, size and turnover rate of an intermediate intracellular pool, and formation of a long-lived intracellular pool comprising FN triphosphates + macromolecules. Such information could be useful in predicting tumor response to 5-FU, formulating protocols that increase delivery of 5-FU into tumor cells, and modulating 5-FU kinetics to overcome tumor resistance.
AB - Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Positron emission tomography (PET) with 5-[18F]FU (PET/5-[18F]FU) is potentially useful for noninvasive measurement of these processes, but is severely hampered by rapid catabolism of 5-[18F]FU in vivo. This study explored the combined use of PET/5-[18F]FU and eniluracil (5-ethynyluracil), a potent inhibitor of 5-FU catabolism, to measure the pharmacokinetics of 5-FU uptake and metabolism in tumors. Rats bearing a s.c. implanted rat colon tumor were given eniluracil and injected i.v. with 5-[18F]FU. Dynamic PET and arterial blood sampling were performed 0-2 h. Tumors (n = 5) were then rapidly excised, frozen, and analyzed for labeled metabolites by high performance liquid chromatography. Tumor TACs were analyzed by compartmental modeling. Compartments were identified with molecular species by comparison with ex vivo assays. Tumor extracellular fluid volume was determined in a separate group of rats. Kinetic analysis indicated partial trapping of 18F within tumors 0-2 h after injection. Tumor time-activity curves conformed closely to a catenary 3-compartment, 5-parameter model. The model yielded values for 5-FU clearance from plasma into the trap that agreed closely with those reported previously for gastrointestinal tumors from a PET/5-[18F]FU + eniluracil study in humans. Tumor extracellular fluid volume as measured with 99mTc DTPA [(3.1 ± 0.2) × 10-1 ml/g; n = 5] agreed well with the distribution volume for compartment 1 of the 3-compartment, 5-parameter model [(3.7 ± 0.3) × 10-1ml/g; n = 5], thus indicating that compartment 1 corresponds to tumor extracellular space. Compartment 3 closely matched the combined magnitudes of 18F fluoro-nucleoside (FN) triphosphates and macromolecules in all of the cases, and compartment 2 was quantitatively consistent with the sum of intracellular 5-FU, FNs, and FN mono- and diphosphates. These observations show that PET/5-[18F]FU combined with an inhibitor of 5-FU catabolism and compartmental modeling is capable of quantifying the following for 5-FU in tumors: distribution volume in the extracellular space, cell transport, size and turnover rate of an intermediate intracellular pool, and formation of a long-lived intracellular pool comprising FN triphosphates + macromolecules. Such information could be useful in predicting tumor response to 5-FU, formulating protocols that increase delivery of 5-FU into tumor cells, and modulating 5-FU kinetics to overcome tumor resistance.
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M3 - Article
C2 - 12839957
AN - SCOPUS:0037742240
SN - 0008-5472
VL - 63
SP - 3667
EP - 3674
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -