NUCLEAR IMAGING OF TUMORS--BIOLOGICAL AND CHEMICAL BASIS

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.