Positron emission tomography (PET) allows one to measure tumor metabolism in vivo and non-invasively. Depending on the tracer employed one can measure a number of metabolic pathways. By labeling chemotherapeutic agents for use with PET one can measure their distribution in vivo. In addition to providing information regarding a specific drug's pharmacodynamics, agents that are retained in biochemical pathways of interest may also be useful in assessing the activity of these pathways in tumors prior to and in response to treatment with other agents. To test this paradigm we have chosen to study [F-18] FAU {1-(2'-deoxy-2'- fluoro-beta-D-arabinofuranosyl)-uracil} for use in PET. This compound is entering phase I trials at our institution. It is an antimetabolite that is incorporated into DNA after sequential activation by thymidine kinase 1 (TK) and thymidylate synthase (TS). We are developing the synthesis of [F-18]FAU to measure the drug retention and use it to assess its kinetics in this pathway. Patients being treated with unlabeled FAU, will be imaged prior to treatment and then re-studied at the time of treatment, by mixing the labeled and therapeutic drugs. This will allow us to calculate the quantity of drug delivered to tumors and normal tissues. We will compare PET results to measurements of TK and TS levels made on tumor specimens. We will construct kinetic models of [F-18]FAU metabolism, as we have done for thymidine, in order to measure the flux through this pathway. To determine the relative contributions of TK and TS to FAU retention we will also study another tracer, [F-18]FLT (3'- deoxy-3'-fluorothymidine), that is specifically retained after phosphorylation by TK. Imaging patients with both tracers will allow us to measure each step in this pathway. The measurement of TS is of particular importance, since preliminary studies show that increased TS levels in tumors may result in 5FU resistance. Furthermore TS is the target of a number of new antineoplastic agents. While [F-18]FAU may find use in measuring the uptake of the therapeutic doses of the drug and activity in the TK and TS pathways, it may also serve as a relative measure of cellular proliferation. Both TK and TS are closely regulated in cells and their activities increase about 10 fold as cells enter the DNA synthetic phase. As such, FAU and FLT when used with PET may provide relative measures of tumor growth and response to therapy. Our proposed study of [F-18]FAU with PET will provide information on the biodistribution of this new therapeutic agent and may provide a way to image tumor TS activity and proliferation.
