""""""""Tumor cell Hypoxia as a Factor in Cancer Therapy"""""""" is a long range project aimed at promoting a more quantitative analysis of the effects of therapeutic perturbations on the dynamics of neoplastic growth. Using a variety of in vivo and in vitro assay procedures (spleen colony assay, serial dilution assay, I125-iododeoxyuridine pre-labelling technique, in vitro colony assay, etc.) an attempt will be made to evaluate the importance of the oxygen effect in radiation therapy and to devise treatment regimens designed to reduce or eliminate the survival advantage of hypoxic tumor cells. Specifically, the effect of simultaneous and sequential administration of hyperthermia and chemical radiosensitizers (electron-affinic agents) on the radiation response of euoxic and hypoxic tumor cells as well as on normal body tissues (bone marrow, skin, intestine) will be investigated. We have previously demonstrated that exposure of tumors to physiologically tolerable doses of nitroimidazoles or hyperthermia produces only modest radiosensitization (dose modifying factor of up to 2.0). However, combined administration of hyperthermia and nitroimidazoles induces very pronounced, synergistic radiosensitization effects with dose modifying factors of 4.3 or higher. This DMF is considerably better than the 3-fold sensitization that could be achieved by full oxygenation of previously hypoxic tumors. Since identical combination treatment produces only modest or no radiosensitization in normal body tissues, the proposed treatment regimen could produce a large therapeutic gain factor in cancer radiation therapy. Our immediate goal is to further investigate the cellular and molecular mechanisms responsible for synergistic radiosensitization, to evaluate the mechanisms responsible for direct cytocidal effects of hyperthermia and electron-affinic agents, and to obtain additional information on environmental and intracellular factors which govern the magnitude of these effects. We also plan to extend this work to newly synthesized electron-affinic agents, to optimize in vivo treatment strategies and modify biological variables (such as tumor pH) in living animals to determine whether such manipulations could further increase radiosensitization of hypoxic tumors without causing undesirable side effects on normal tissues of the host.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA021673-09
Application #
3165620
Study Section
Radiation Study Section (RAD)
Project Start
1978-08-01
Project End
1989-07-31
Budget Start
1987-08-01
Budget End
1989-07-31
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Florida State University
Department
Type
Schools of Arts and Sciences
DUNS #
020520466
City
Tallahassee
State
FL
Country
United States
Zip Code
32306
Hofer, K G; Lin, X; Bao, S (1996) DNA damage, micronucleus formation, and cell death from 125I decays in DNA. Acta Oncol 35:825-32
Hofer, K G (1996) Biophysical aspects of Auger processes--A review. Acta Oncol 35:789-96
Ludwikow, G; Hofer, K G; Bao, S P et al. (1996) The effect of 125I decay at different stages of S-phase on survival, expression of micronuclei and chromosome aberrations in CHO cells. Int J Radiat Biol 70:177-87
Hofer, K G; Bao, S P (1995) Low-LET and high-LET radiation action of 125I decays in DNA: effect of cysteamine on micronucleus formation and cell killing. Radiat Res 141:183-92
Charlton, D E; Hofer, K G; Vanloon, N et al. (1994) Double-strand breaks from 125I incorporated in the DNA and cell death. Int J Radiat Biol 66:437-40
Hofer, K G; van Loon, N; Schneiderman, M H et al. (1993) Targets for radiation-induced cell death: target replication during the cell cycle evaluated in cells exposed to X-rays or 125I decays. Int J Radiat Biol 64:205-16
Hofer, K G; van Loon, N; Schneiderman, M H et al. (1992) The paradoxical nature of DNA damage and cell death induced by 125I decay. Radiat Res 130:121-4
Schneiderman, M H; Hofer, K G; Schneiderman, G S (1991) An in vitro 125IUdR-release assay for measuring the kinetics of cell death. Int J Radiat Biol 59:397-408
Schneiderman, M H; Hofer, K G; Schneiderman, G S (1990) Association between the division delay target and DNA late in the cell cycle. Radiat Res 122:337-40
Hofer, K G; Lakkis, M; Hofer, M G (1989) Cytocidal effects of misonidazole, Ro 03-8799, and RSU-1164 on euoxic and hypoxic BP-8 murine sarcoma cells at normal and elevated temperatures. Cancer 63:1501-8

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