The long term 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. There are two general aims. The first is to study dose-time effect in relation to the proliferative status of cells. Specifically, we would (1) measure dose response and dose rate effects for delays in the transition from the noncycling to cycling state of normal human cells in culture; (2) map the G0/G1 x-ray transition delay point with respect to sequential biochemical events known to accompany the transition, and (3) develop a DNA polymerase alpha monoclonal antibody staining technique to determine """"""""growth fraction"""""""" in dog tumors and possible changes ingrowth fraction and the proportion of cycling cells in some normal tissues during radiotherapy. The second general aim is to continue studies on the genetic control of cellular responses to radiation and hyperphermia. Specifically, this would involve (4) continuing attempts to isolate and characterize x-ray sensitive mutants of OHO cells; (5) isolation"""""""" and characteristion of additional CHO mutants that are deffective in their ability to develop thermotolerance; (6) carry but complementation analyses is cell hybrids among mutants isolated in (4) and (5) above; (7) map genes controlling radiation and heat sensitivity with respect to their location on human chromosomes in CHO/human hybrids and (8) isolate mutants deficient in (a) DNA Polymerase beta and (b) glutathione or glutathione transferase to assess the role of these in modulating cellular responses to free radical generating agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA018023-21
Application #
2086654
Study Section
Special Emphasis Panel (NSS)
Project Start
1975-06-01
Project End
1997-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
21
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Radiation-Diagnostic/Oncology
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
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; 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
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
Amdur, R J; Bedford, J S (1994) Dose-rate effects between 0.3 and 30 Gy/h in a normal and a malignant human cell line. Int J Radiat Oncol Biol Phys 30:83-90

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