Positron emission tomography (PET) offers the opportunity to measure tumor metabolism in vivo. PET utilizes quantitative measurements of positron-labeled biochemical tracers, and kinetic models to measure discrete metabolic processes in normal and pathologic tissues. C-11-labeled thymidine (Tdr) is a potential imaging agent for PET, which we plan to develop and test for the eventual purpose of quantitating tumor growth. Unlike other tracers used for PET (e.g. glucose, amino acids), thymidine has a unique potential for quantitating DNA synthesis in vivo. As a precursor in DNA synthesis, Tdr has found widespread use in the quantitation of cell growth in vitro. In contrast, its application to in vivo measurements will require a more detailed knowledge of the biochemistry and kinetics of its uptake. For the most part, such developmental studies are more readily conducted utilizing H-3 or C-11 labeled Tdr analyzed in tissue culture, excised tissues and isolated organs. Despite extensive study of Tdr metabolism over the years, key problems still remain to be answered to properly interpret the measurement of in vivo Tdr uptake. These problems are: 1) To calculate DNA synthetic rates, the relative utilization of endogenous and exogenous Tdr must be known. We plan to study this by using a Tdr analog, BudR, to measure the contribution of exogenously introduced Tdr. The importance of reutilization of Tdr released by dying cells will also be studied, since this will affect the size of exogenous pools. 2) The available kinetic models of thymidine metabolism have not been tested for in vivo use. In order to further develop and validate these models we will obtain detailed measurements of the time course of Tdr uptake and degradation in vivo. 3) Previous comparisons between the measurement of labeled Tdr uptake in vivo and more conventional measurements of cellular proliferation may not have been done under optimal conditions, since no attempt was made to measure DNA synthesis. We plan to make such comparisons after we have gained further understanding of the kinetics of Tdr metabolism. The long range goal of this work is to apply measurements of Tdr uptake with PET to monitoring tumor growth and response to cytotoxic therapy in vivo. To achieve this goal, we plan to conduct these """"""""pre-imaging"""""""" PET studies to develop biochemical and kinetic models of Tdr metabolism which will be necessary to convert the raw imaging data obtained with PET into quantitative measurements of regional cellular proliferation.
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