The objective of these studies is systematic development of radiopharmaceuticals for imaging hypoxic, radiation resistant cells in tumors. The approach is based on the principle of specific metabolic trapping of certain classes of drugs in viable cells at low p0/2, particularly nitroimidazoles but possibly also bioreductive alkylating agents such as naturally occurring quinones (porfiromycin, adriamycin), synthetic quinones, nitrobenzyl compounds and others. Drugs chosen for study are available labeled with H-3 or C-14 or will be radiolabeled in our laboratory. The dependency of radiolabeled drug retention on concentration of 0/2, drug, and reductase enzymes will be measured in rodent tumor cells in vitro and tumors in vivo. The relationship between tumor blood flow and radiotracer retention will be studied, and glucose metabolism will be investigated in those cells identified by the hypoxia tracer. Several well characterized tumors, each of which grows both in vitro and in vivo, are available for these studies. Hypoxic cells are presumed to exist at a lower redox potential than well oxygenated cells. Therefore, a basic hypothesis being tested is that reduction potential of an imaging agent will be a major determinant of whether it binds stably in cells at a particular p0/2. Partition coefficient will affect drug metabolism, delivery to tissues with low blood flow, and plasma clearance time. It is hypothesized that an optimum partition coefficient can be identified for drugs in a particular class, allowing high uptake in tumor but still giving rapid enough plasma clearance to be compatible with imaging. Thus, chemical properties of reduction potential, partition coefficient, and pk/a will be measured for selected drugs and correlated with the 0/2 dependency of binding in the tumor systems. A final test of selected hypoxia imaging drugs will be how well they track changes in the proportion of hypoxic tumor cells and in radiosensitivity following treatments that either increase or decrease tumor hypoxia. The long term goal is to use these agents to monitor radioresistant hypoxic cell in human tumors, using positron labeled drugs and positron emission tomography, and to apply this information to improving radiotherapy.
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