The long-term goal of this project is to obtain radiobiological information pertinent to the improvement of controlling human tumors by radiotherapy alone or combined with adjuvants such as hyperthermia. Blood flow in the tissues, including tumors, markedly influences the tissue damage by radiation because the supply of oxygen, the most potent modifier of radiation effect, is largely dependent on blood flow. It has been known that the intratissue microenvironment, such as the acidity and nutritional supply, greatly affects the thermosensitivity of the tissues. Those microenvironmental factors are also closely influenced by the blood flow. In addition, the thermal profile in tissues during heating is directly related to the heat dissipation by blood flow. These facts clearly indicate that blood flow plays a cardinal role in the response of tissues to radiation and hyperthermia. An immediate aim of this proposal is to elucidate the relationship between the change in blood flow and that in the intratissue microenvironmental factors, such as pH and pO2, by radiation and hyperthermia alone or combined. Indications are that blood vessels become resistant to heat stress when they are repeatedly heated.
The second aim of the proposal is to study the possible development of thermotolerance in the vascular system in vivo and in endothelial cells in vitro. Indications are that the presence of hypoxic cells might be a limiting factor for complete control of certain human tumors. One of the aims of this proposal is to investigate the potential usefulness of perfluorochemicals to improve tumor oxygenation for better tumor control by radiotherapy. RIF-1 tumor of C3H mice and SCK tumors of A/J mice will be used as tumor model and the skin muscle of mouse legs will be used as the normal tissue models. Tissue pH and pO2 will be measured with the microelectrode method. The Rb-86 methods and laser Doppler methods will be used for measurement of blood flow.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Radiation Study Section (RAD)
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University of Minnesota Twin Cities
Schools of Medicine
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Song, C W; Shakil, A; Osborn, J L et al. (2009) Tumour oxygenation is increased by hyperthermia at mild temperatures. 1996. Int J Hyperthermia 25:91-5
Monzen, Hajime; Griffin, Robert J; Williams, Brent W et al. (2004) Study of arsenic trioxide-induced vascular shutdown and enhancement with radiation in solid tumor. Radiat Med 22:205-11
Griffin, R J; Monzen, H; Williams, B W et al. (2003) Arsenic trioxide induces selective tumour vascular damage via oxidative stress and increases thermosensitivity of tumours. Int J Hyperthermia 19:575-89
Griffin, Robert J; Williams, Brent W; Wild, Robert et al. (2002) Simultaneous inhibition of the receptor kinase activity of vascular endothelial, fibroblast, and platelet-derived growth factors suppresses tumor growth and enhances tumor radiation response. Cancer Res 62:1702-6
Song, C W; Park, H; Griffin, R J (2001) Improvement of tumor oxygenation by mild hyperthermia. Radiat Res 155:515-28
Park, H J; Lyons, J C; Ohtsubo, T et al. (2000) Cell cycle progression and apoptosis after irradiation in an acidic environment. Cell Death Differ 7:729-38
Griffin, R J; Ogawa, A; Song, C W (2000) A novel drug to reduce tumor perfusion: antitumor effect alone and with hyperthermia. Radiat Res 154:202-7
Ogawa, A; Griffin, R J; Song, C W (2000) Effect of a combination of mild-temperature hyperthermia and nicotinamide on the radiation response of experimental tumors. Radiat Res 153:327-31
Park, H; Lyons, J C; Griffin, R J et al. (2000) Apoptosis and cell cycle progression in an acidic environment after irradiation. Radiat Res 153:295-304
Shakil, A; Osborn, J L; Song, C W (1999) Changes in oxygenation status and blood flow in a rat tumor model by mild temperature hyperthermia. Int J Radiat Oncol Biol Phys 43:859-65

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