Our overall goal is to use Positron emission tomography (PET) to develop an understanding of the response of cancers to therapy using non-invasive quantitative imaging of biochemistry. PET must be combined with the appropriate positron-labeled compound in order to measure the metabolic pathway of interest. 11C- thymidine (labeled in the methyl position) is a PET imaging agent which has the potential for quantitating DNA synthesis in vivo. Our ongoing studies (including those funded by this grant) demonstrate that PET imaging with 11C-thymidine (TdR) is feasible. We have already addressed a number of the problems associated with interpreting the PET images of 11C-TdR including the contributions to TdR metabolism of intracellular pools, reutilization and degradation. This proposal addresses areas of research needed to gain further insight into the biochemistry and kinetics of TdR metabolism. These studies are needed to assist in converting the simple measurement of time-dependent tissue radioisotope concentration obtained by the tomograph into quantitative measurements of cellular proliferation. In our effort to test the hypothesis that the measurement of TdR uptake will be useful in the quantitation of tumor growth, we will address the following problems: 1) In order to interpret PET images one must know the amount of labeled precursor delivered to the tumor. Therefore, we will develop techniques and models which will account for the proportion of native TdR compound remaining in the circulation. We will also study the first pass extraction of TdR and the distribution of the metabolites of TdR. 2) Refinement of the kinetic models of TdR metabolism is needed. The data we are accumulating with PET will be fitted using compartmental, graphical and sliding segment modeling approaches. We will compare the results of the kinetic models to direct measurements of the incorporation of TdR into DNA at biopsy. 3) Validation of the measurements made with PET is essential. This will be done in dogs with metastatic lymphoma, where biopsy specimens will be analyzed using a number of cellular and biochemical techniques for correlation with the PET measurements. The ultimate goal of our group is to develop an understanding of the response of cancer to therapy using 11C-TdR and PET. In order to make meaningful measurements of cellular proliferation using 11C-TdR and PET we need to produce detailed biochemical and kinetic models of TdR metabolism.
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