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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA055893-04A2
Application #
2396742
Study Section
Radiation Study Section (RAD)
Project Start
1993-05-01
Project End
2000-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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Iyer, R V; Haynes, P T; Schneider, R F et al. (2001) Marking hypoxia in rat prostate carcinomas with beta-D-[125I]azomycin galactopyranoside and. J Nucl Med 42:337-44
Chapman, J D; Schneider, R F; Urbain, J L et al. (2001) Single-photon emission computed tomography and positron-emission tomography assays for tissue oxygenation. Semin Radiat Oncol 11:47-57
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Chapman, J D; Coia, L R; Stobbe, C C et al. (1996) Prediction of tumour hypoxia and radioresistance with nuclear medicine markers. Br J Cancer Suppl 27:S204-8
Yeh, K A; Biade, S; Lanciano, R M et al. (1995) Polarographic needle electrode measurements of oxygen in rat prostate carcinomas: accuracy and reproducibility. Int J Radiat Oncol Biol Phys 33:111-8
Joseph, P; Jaiswal, A K; Stobbe, C C et al. (1994) The role of specific reductases in the intracellular activation and binding of 2-nitroimidazoles. Int J Radiat Oncol Biol Phys 29:351-5