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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Torres-Anjel, Manuel J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Schools of Medicine
United States
Zip Code
Schwartz, Jeffrey L; Tamura, Yasuko; Jordan, Robert et al. (2004) Effect of p53 activation on cell growth, thymidine kinase-1 activity, and 3'-deoxy-3'fluorothymidine uptake. Nucl Med Biol 31:419-23
Grierson, John R; Schwartz, Jeffery L; Muzi, Mark et al. (2004) Metabolism of 3'-deoxy-3'-[F-18]fluorothymidine in proliferating A549 cells: validations for positron emission tomography. Nucl Med Biol 31:829-37
Rajendran, J G; Wilson, D C; Conrad, E U et al. (2003) [(18)F]FMISO and [(18)F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression. Eur J Nucl Med Mol Imaging 30:695-704
Schwartz, Jeffrey L; Tamura, Yasuko; Jordan, Robert et al. (2003) Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. J Nucl Med 44:2027-32
Rasey, J S; Casciari, J J; Hofstrand, P D et al. (2000) Determining hypoxic fraction in a rat glioma by uptake of radiolabeled fluoromisonidazole. Radiat Res 153:84-92
Rasey, J S; Hofstrand, P D; Chin, L K et al. (1999) Characterization of [18F]fluoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia. J Nucl Med 40:1072-9
Schwartz, J L; Rasey, J; Wiens, L et al. (1999) Functional inactivation of p53 by HPV-E6 transformation is associated with a reduced expression of radiation-induced potentially lethal damage. Int J Radiat Biol 75:285-91
Maurer, B J; Ihnat, M A; Morgan, C et al. (1999) Growth of human tumor cells in macroporous microcarriers results in p53-independent, decreased cisplatin sensitivity relative to monolayers. Mol Pharmacol 55:938-47
Tewson, T J (1997) Synthesis of [18F]fluoroetanidazole: a potential new tracer for imaging hypoxia. Nucl Med Biol 24:755-60
Rasey, J S; Cornwell, M M; Maurer, B J et al. (1996) Growth and radiation response of cells grown in macroporous gelatin microcarriers (CultiSpher-G). Br J Cancer Suppl 27:S78-81

Showing the most recent 10 out of 19 publications