The principal objective of this proposal is to gain a better understanding of factors governing cellular responses to ionizing radiation as they bear on dose rate and dose fractionation effects of interest for radiation oncology and issues of low level radiation hazards to humans. Repair processes, the intrinsic sensitivity of cells, and their proliferative status are factors which would be studied. Because confluent cultures nontransformed cells and their transformed counter parts display certain characteristics akin to cell populations in at least some normal tissues and tumors, respectively, we plan to examine and compare responses in such systems, particularly C3H10T1/2 cells, with respect to relationships among radiation dose, dose-rate, dose fractionation, the kinetics of cell turnover, and the repair of potentially lethal damage. The significance of these studies bears directly on currently debated views concerning the cellular basis underlying differences in isoeffect curves of dose-per-fraction vs. total dose for late and early responding (tumor?) tissues. This, in turn, would directly address the issue of whether there is a biological basis at the cellular level to support the notion that hyperfractionation or accelerated fractionation might have clinical advantages over standard fractionation in the treatment of cancer patients. Another portion of this study involves the isolation and characterization of x-ray sensitive and thermotolerantless mammalian cell mutants. The comparative responses of such mutants and their wild-type counterparts would allow identification of defects present in mutant cells and, thus, factors which control these responses in wild-type cells. Repair and cell cycle dependent responses would be studied in x-ray sensitive mutants. In thermotolerantless mutants the development of heat-shock proteins (or lack thereof) would be examined. Thermotolerance is, potentially, an important factor in cancer treatment by hyperthermia, either alone or in combination with drugs or radiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA018023-14
Application #
3164829
Study Section
Radiation Study Section (RAD)
Project Start
1975-06-01
Project End
1989-05-31
Budget Start
1988-06-01
Budget End
1989-05-31
Support Year
14
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Type
Schools of Veterinary Medicine
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Priestley, A; Beamish, H J; Gell, D et al. (1998) Molecular and biochemical characterisation of DNA-dependent protein kinase-defective rodent mutant irs-20. Nucleic Acids Res 26:1965-73
Lin, J Y; Bedford, J S (1997) Regional gene mapping using mixed radiation hybrids and reverse chromosome painting. Radiat Res 148:405-12
Lin, J Y; Muhlmann-Diaz, M C; Stackhouse, M A et al. (1997) An ionizing radiation-sensitive CHO mutant cell line: irs-20. IV. Genetic complementation, V(D)J recombination and the scid phenotype. Radiat Res 147:166-71
Muhlmann-Diaz, M C; Dullea, R G; Bedford, J S (1996) Application of 5-bromo-2'deoxyuridine as a label for in situ hybridization in chromosome microdissection and painting, and 3' OH DNA end labeling for apoptosis. Biotechniques 21:82-6
Schneiderman, M H; Schneiderman, G S; Muhlmann-Diaz, M C et al. (1996) The presence of DNA breaks and the formation of chromatid aberrations after incorporation of 125IdUrd may be necessary but are not sufficient to block cell cycle progression in G2 phase. Radiat Res 145:17-23
Muhlmann-Diaz, M C; Bedford, J S (1995) Comparison of gamma-ray-induced chromosome ring and inversion frequencies. Radiat Res 143:175-80
Jha, M N; Bamburg, J R; Bedford, J S (1994) Cell cycle arrest by Colcemid differs in human normal and tumor cells. Cancer Res 54:5011-5
Stackhouse, M A; Bedford, J S (1994) An ionizing radiation-sensitive mutant of CHO cells: irs-20. III. Chromosome aberrations, DNA breaks and mitotic delay. Int J Radiat Biol 65:571-82
Muhlmann-Diaz, M C; Bedford, J S (1994) Breakage of human chromosomes 4, 19 and Y in G0 cells immediately after exposure to gamma-rays. Int J Radiat Biol 65:165-73
Smith, N N; Harvey, W F; Bedford, J S et al. (1994) Heat protection by deuterium oxide of heat sensitive and wild-type Chinese hamster ovary cells. Int J Hyperthermia 10:73-8

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