It is believed that elimination of hypoxic protection of human tumors significantly increases the probability of achieving complete tumor cure by radiotherapy. Recently the applicants have realized that heating rodent tumors in the 40-42oC range can cause significant increase in tumor oxygenation, most likely by increasing blood flow. It is hypothesized that i) modest temperature hyperthermia (MTH) is clinically useful in improving oxygenation in tumors., and ii) that the combination of MTH(increase blood flow) with carbogen breathing (increase O2 content in blood) may effectively increase tumor oxygenation. The combination of MTH with other agents which increase tumor blood flow, such as nicotinamide and pentoxyphylline, may also be potentially useful means to increase tumor oxygenation. The goal of this investigation is to reveal the efficacy of MTH at 40.5-42.5oC alone or in combination with the other agents in increasing tumor oxygenation and increasing the response of tumors to radiotherapy. This would be significant since these temperatures are easily achievable in the clinic. FSaII tumors of C3H mice, SCK tumors of A/J mice and R3230 A C tumors of Fischer rats will be used. The tumor oxygenation status will be assessed from pO2 values determined with the Eppendorf pO2 Histograph, hypoxic cell fractions in the tumors with the paired radiation cell survival curve method, and an immunohistochemical method using a fluorinated etanidazole analog (EF5). The response of the tumor to treatment will be assessed from the tumor growth delay and tumor cure (TCD50). From the increase in tumor response and the increase in damage in normal tissue (foot), the therapeutic value of MTH alone or in combination with other agents will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA013353-26
Application #
2894448
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1977-09-30
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
26
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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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