IN SITU MEASUREMENT OF CHEMOTHERAPEUTIC DRUG KINETICS IN SOLID TUMORS

长期目标是发展一种测量方法

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. Several years ago, researchers at Roswell Park Cancer Institute (Buffalo, NY) and Burroughs-Wellcome Co. (subsequently changed to Glaxo-Wellcome) began reporting 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 or more. This study seeks to develop and validate the necessary kinetic imaging and mathematical modeling techniques in a rat, colorectal 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. Positive results in the experimental rat study are expected to lead to a clinical trial of PET/[18F]5-FU 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. Dr. Bading is collaborating with Prof. Walter Wolf, USC B00. of Pharmaceutical Sciences, a leading expert in the in vivo study of 5-FU pharmacokinetics by magnetic resonance spectroscopy (MRS). Together, Drs. Bading and Wolf are developing the combined use of PET and MRS to maximize capability for noninvasive characterization of 5-FU kinetics in experimental models and human patients. The objectives of the project are summarized below. Specific Aims 1 and 2 have been completed; work on Specific Aim 3 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 wk 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.