The long range objective is to develop a method for measuring tumor uptake and metabolic incorporation of 5-fluorouracil (5-FU) in human tumors by positron emission tomography (PET). Fluorouracil is readily labeled with the positron-emitting radionuclide 18F, and PET studies with [18F]5-FU in human cancer patients have been reported. However, interpretation of scan results is obscured by the presence of labeled, recirculating catabolites of [18F]5-FU. Researchers at Burroughs-Wellcome Co. recently reported marked increases in the effectiveness of 5-FU against mouse and rat tumors when the drug is given in combination with 5-ethynyluracil (5-EU), an inhibitor of dihydropyrimidine dehydrogenase (DPD), the enzyme which catalyzes the first step in the catabolic breakdown of 5-FU within the body. Phase I clinical trials of 5-FU+5-EU have yielded positive results. With catabolism suppressed by 5-EU, PET imaging of [18F]5-FU could be used to accurately quantify tumor incorporation of 5-FU into cytotoxic molecular species, which are retained intracellularly for several hours are more. This study seeks to develop and validate the necessary kinetic imaging and mathematical modeling techniques in a rat, colo-rectal tumor model. Technical support for the modeling effort is provided by the Center for Bioengineering, University of Washington. Even though it is one of the most widely used chemotherapeutic drugs, the clinical efficacy of 5-FU is highly limited. Combination with 5-EU may render 5-FU far more effective. The ability to measure tumor incorporation of 5-FU noninvasively would also be a major advance, since it would permit individualized treatment planning and identification of those patients unlikely to respond because of inadequate tumor incorporation of 5-FU. If positive results are obtained in the experimental rat study, PET/[18F]5-FU measurements will be performed in a special Phase II clinical trial of 5-FU+5-EU at USC. However, the rat study will itself add significant information about the pharmacokinetics of 5-FU + 5-EU and the usefulness of PET for pharmacokinetic studies, regardless of subsequent studies in humans. The objectives of the project are summarized below.
Specific Aim 1 has been completed, and work on Specific 2 is in progress.
Specific Aim 1 : Demonstrate sensitivity of rat tumor to 5-FU + 5-EU. When subcutaneously implanted tumors have grown to 5 g, the rats will be treated with i.v. 5-FU alone or i.v. 5-FU + i.p. 5-EU using doses and schedule specified by Burroughs Wellcome. Tumor size will be measured periodically during a 2 week follow-up period to determine response to therapy.
Specific Aim 2 : Develop techniques for tracer kinetic studies in rats. (physiologic control, vascular access, alignment in PET scanner, validation of quantitative imaging, labeled metabolite identification by HPLC).
Specific Aim 3 : Use PET, [18F] 5-FU and mathematical modeling to measure 5-FU trapped/g tumor. when 5-FU is given with or without 5-EU). Rats will be pretreated or not with 5-EU (1 mg/kg i.p.). Dynamic imaging and serial arterial blood sampling will be performed for 2 h following bolus i.v. injection of [18F]5-FU. Radio- and HPLC assays will be done on the blood samples as well as tumor tissue excised at the end of the imaging procedure. The resulting data will be used to develop and validate a kinetic model which correctly predicts the amount of 5-FU incorporated into cytotoxic forms within tumor.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Bassingthwaighte, James B; Butterworth, Erik; Jardine, Bartholomew et al. (2012) Compartmental modeling in the analysis of biological systems. Methods Mol Biol 929:391-438
Dash, Ranjan K; Bassingthwaighte, James B (2010) Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng 38:1683-701
Bassingthwaighte, James B; Raymond, Gary M; Butterworth, Erik et al. (2010) Multiscale modeling of metabolism, flows, and exchanges in heterogeneous organs. Ann N Y Acad Sci 1188:111-20
Dash, Ranjan K; Bassingthwaighte, James B (2006) Simultaneous blood-tissue exchange of oxygen, carbon dioxide, bicarbonate, and hydrogen ion. Ann Biomed Eng 34:1129-48
Dash, Ranjan K; Bassingthwaighte, James B (2004) Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng 32:1676-93
Kellen, Michael R; Bassingthwaighte, James B (2003) Transient transcapillary exchange of water driven by osmotic forces in the heart. Am J Physiol Heart Circ Physiol 285:H1317-31
Kellen, Michael R; Bassingthwaighte, James B (2003) An integrative model of coupled water and solute exchange in the heart. Am J Physiol Heart Circ Physiol 285:H1303-16
Wang, C Y; Bassingthwaighte, J B (2001) Capillary supply regions. Math Biosci 173:103-14
Swanson, K R; True, L D; Lin, D W et al. (2001) A quantitative model for the dynamics of serum prostate-specific antigen as a marker for cancerous growth: an explanation for a medical anomaly. Am J Pathol 158:2195-9
Swanson, K R; Alvord Jr, E C; Murray, J D (2000) A quantitative model for differential motility of gliomas in grey and white matter. Cell Prolif 33:317-29

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