Recent studies with both rodent and human tumors utilizing oxygen electrodes, 31P-NMR spectroscopy, sensitizer adducts and tumor perfusion measures by 99m/Tc-HMPAO show solid tumor oxygenation status to be extremely heterogeneous. To date, this tumor property cannot be estimated from histology, size nor growth rate and must be measured for each individual tumor. The proposed research will build upon our discovery and experience with nitroaromatic drugs which were shown to be reduced intra- cellularly at rates inversely proportional to cellular oxygen concen- tration producing adducts to cellular biomolecules indicative of intra- cellular oxygen tension and radiosensitivity. Autoradiography and liquid scintillation counting of beta-labelled sensitizer adducts are now accepted techniques for measuring relative oxygenation status in both rodent and human tumors. gamma-emitting radionuclides attached to appropriate bioreductive drugs could provide useful non-invasive measures of this tumor property. Previous research at the Cross Cancer Institute (Edmonton, Canada) had identified iodinated azomycin nucleosides as possible candidates for such nuclear medicine probes. Iodinated azomycin arabinoside (IAZA) has been administered to 40 patients before and/or during tumor therapy. While tumor retention of IAZA probably indicates low oxygen levels in some human tumors, this imaging compound Is far from optimum. The clearance and excretion of unbound marker is prerequisite for developing an optimal image of bound sensitizer in hypoxic tissue. The plasma half-life of IAZA in humans is about 10 hr. In addition, Its dehalogenation and hepatobiliary excretion results in isotope image unrelated to tissue bioreductive status. This research will synthesize novel hypoxic markers of the bioreductively-activated ligating (BRAL) class and determine structure/activity relationships in animal models for selecting improved compounds with shorter plasma half-lives and with iodine more resistant to pharmacologic dehalogenation. The hypoxic marking ability of superior compounds will be tested and compared with a radiosensitivity measure of individual EMT-6 tumors and with a radiosensitivity measure and the 31P-NMR spectra of individual Dunning 3327-AT rat prostate tumors. Both animal tumor models display a wide heterogeneity of oxygenation status. These correlative studies will assist in defining an Improved probe for the non-invasive measurement of solid tumor oxygenation. The emphasis of this research is the identification of an improved marker with which clinical scientists can make reliable non-invasive measures of human tumor oxygenation and reoxygenation.
