Tumor angiogenesis, vascularization, blood flow and oxygen consumption will ultimately determine the nutritional status of and the oxygen delivery to solid tumors essential for their growth. The oxygen concentration within clonogenic tumor cells exhibits both inter- and intra-tumor heterogeneity and is an important determinant for treatment response to radiotherapy and some chemotherapy. There is no standard procedure in clinical use today for measuring this tumor property. For practical reasons, a non-invasive assay which uses equipment available in most cancer centers would be preferred. Some bioreducible drugs may provide for that attractive option. Nitroaromatic compounds are enzymatically reduced within living cells to activated intermediates which become covalently bound to cellular molecules at rates inversely proportional to intracellular oxygen concentration. When labeled with appropriate isotopes, adducted marker can be detected by various imaging procedures. Nitroimidazole-based markers have been used to detect hypoxic cells within rodent and human tumors by autoradiography and immunofluorescence assays of tissue sections and by nuclear medicine imaging techniques. This research project has now synthesized and characterized novel, second-generation nuclear medicine markers with increased water solubility and improved marking potential. Even better hypoxic markers of the azomycin-nucleoside, azomycin-aromatic and azomycin-chelate classes can now be designed and synthesized. Optimal markers of each class will be validated in appropriate tumor models by independent measurements of their physiology (their P-31 NMR spectra), their oxygen levels by microelectrode and their intrinsic radioresistance. In addition, the sensitivity of optimal hypoxic markers for measuring oxygenation change in individual tumors will be determined. This research will define improved nuclear medicine hypoxic markers for human cancer investigations. The optimal marker(s) will be used to 1) determine the role of initial tumor oxygenation in predicting treatment response, 2) measure reoxygenation kinetics in human tumors during treatment and 3) identify subsets of radioresistant tumors for which hypoxia-targeted therapies are indicated.
