title: Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma: a positron emission tomography study in rats.
abstract: Drug uptake and anabolism by tumors are prerequisites of response to 5-fluorouracil (5-FU). Positron emission tomography (PET) with 5-[(18)F]FU (PET/5-[(18)F]FU) is potentially useful for noninvasive measurement of these processes, but is severely hampered by rapid catabolism of 5-[(18)F]FU in vivo. This study explored the combined use of PET/5-[(18)F]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-[(18)F]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 (18)F 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-[(18)F]FU + eniluracil study in humans. Tumor extracellular fluid volume as measured with (99m)Tc DTPA [(3.1 +/- 0.2) x 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) x 10(-1) ml/g; n = 5], thus indicating that compartment 1 corresponds to tumor extracellular space. Compartment 3 closely matched the combined magnitudes of (18)F fluoronucleoside (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-[(18)F]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.
authors.affiliation: PET Imaging Science Center, Department of Radiology, University of Southern California, Los Angeles, California 90033, USA. jbading@usc.edu
authors.forename: James R
authors.initials: JR
authors.lastname: Bading
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yoo
authors.forename: John D
authors.initials: JD
authors.lastname: Fissekis
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.forename: David Z
authors.initials: DZ
authors.lastname: D'Argenio
authors.forename: Peter S
authors.initials: PS
authors.lastname: Conti
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging*; D000818:Animals; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging*; D004195:Disease Models, Animal; D005260:Female; D005462:Fluorine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics*; D007700:Kinetics; D008954:Models, Biological; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D005462:Fluorine Radioisotopes; D005472:Fluorouracil