Normal and tumor tissue hypoxia is associated with heart attack, stroke and cancer and may be a key factor in diabetes and alcohol-induced liver disease. Cancer specialists have long been interested in tissue hypoxia because hypoxic cells are radioresistant due to altered free radical chemistry and chemoresistant due low drug concentration in hypoxic cells that are at or near the limit of drug diffusion. On a more positive note, hypoxic tumor cells might be targets for improved therapy through bioreductive strategies. Finally, hypoxia (or hypoxia/reperfusion) is now recognized as a stress leading to gene expression in normal and tumor tissue that can be beneficial or harmful depending on circumstances. With the heightened interest in hypoxia in both normal and tumor tissue has come an urgent need for versatile and reliable methods for measuring tissue oxygenation. Many techniques have been proposed including hypoxia markers and oxygen microelectrodes. The primary goal of the present proposal is to make the first direct comparison between these two techniques in human tumors in collaboration with investigators at Aarhus University Hospital in Aarhus, Denmark. Such a comparison was called for in a 1992 NIH Oxygen Workshop. Our hypoxia marker will be injected into patients and 8 hours later oxygen electrode measurements made in the tumor followed by tissue biopsy for hypoxia marker binding by immunohistochemical analysis. The hypoxia marker approach lends itself to comparison with other features of tumor physiology related to therapeutic response. One such comparison to be carried out on the same biopsy sample will be with tumor cell proliferation (Ki-67). We believe that the hypoxia marker technique will be useful in radiation and chemotherapy treatment planning; for studies of tissue oxygenation in models of normal tissue pathologies; and, for relating hypoxia to the expression of stress proteins on a microregional basis.
| Raleigh, J A; Chou, S C; Bono, E L et al. (2001) Semiquantitative immunohistochemical analysis for hypoxia in human tumors. Int J Radiat Oncol Biol Phys 49:569-74 |
| Raleigh, J A; Chou, S C; Calkins-Adams, D P et al. (2000) A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. Clin Cancer Res 6:855-62 |
| Raleigh, J A; Chou, S C; Arteel, G E et al. (1999) Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat Res 151:580-9 |
| Raleigh, J A; Chou, S C; Tables, L et al. (1998) Relationship of hypoxia to metallothionein expression in murine tumors. Int J Radiat Oncol Biol Phys 42:727-30 |
