The goal of this research is to understand the relationships between the induction and subsequent repair of the lesions produced in DNA after exposure of mammalian cells to ionizing radiation, and radiobiological factors observed at the cell or tissue level which are thought to be important to human cancer radiotherapy. These include cell recovery mechanisms, the role of O2 tension at the time of irradiation, and possible differences in radiosensitivity between tumor cells and normal cells. The approach to these questions involves testing specific aspects of these relationships in model systems, initially in DNA-repair deficient cells exposed in vitro, and then in mouse model tumors irradiated in vivo. The proposed studies are divided into 3 specific aims. The first is to isolate and characterize radiaiotn- sensitive mutant cell lines of Chinese hamster cells so that the different enzymatic pathways involved in the repair of radiaiton- induced DNA damage can be determined. The nature of the repair defects will be examined in terms of the relative ability of the mutant lines to rejoin single- and double-stand breaks. Differences in repair at the DNA level will be compared to the ability of the lines to repair sub- and potentially-lethal damage.
Aim 2 involves an identification of radiation-induced lesions in DNA and an evaluation of their role in cell killing. New modifications of the alkaline and neutral filter techniques will be used to assay changes in the spectrum of lesions induced under different oxygen tensions and examine the mutant lines from aim 1 for defects in repair of different types of strand breaks. Finally, in aim 3, possible differences in repair kinetics between proliferating and non-proliferating cells will be further characterized in bone marrow, testes and mouse mammary adenocarcinoma tumor cells irradiated in vivo using alkaline elution coupled with both fluorometric and radioactive DNA assays. Hopefully, the results of these investigations may ultimately provide knowledge useful for improving the treatment of human cancer by radiation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA026312-07A1
Application #
3167247
Study Section
Radiation Study Section (RAD)
Project Start
1979-07-01
Project End
1990-12-31
Budget Start
1987-07-01
Budget End
1988-12-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Hospitals
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Story, M D; Mendoza, E A; Meyn, R E et al. (1994) Pulsed-field gel electrophoretic analysis of DNA double-strand breaks in mammalian cells using photostimulable storage phosphor imaging. Int J Radiat Biol 65:523-8
Story, M D; Garrett, K C; Tofilon, P J et al. (1993) Influence of irradiation conditions on the measurement of DNA double-strand breaks by pulsed-field gel electrophoresis. Int J Radiat Biol 63:297-304
Meyn, R E; Murray, D; vanAnkeren, S C et al. (1991) Isolation and characterization of nitrogen mustard-sensitive mutants of Chinese hamster ovary cells. Mutat Res 254:161-5
Dolf, G; Meyn, R E; Curley, D et al. (1991) Extrachromosomal amplification of the epidermal growth factor receptor gene in a human colon carcinoma cell line. Genes Chromosomes Cancer 3:48-54
vanAnkeren, S C; Murray, D; Meyn, R E (1988) Induction and rejoining of gamma-ray-induced DNA single- and double-strand breaks in Chinese hamster AA8 cells and in two radiosensitive clones. Radiat Res 116:511-25
vanAnkeren, S C; Murray, D; Stafford, P M et al. (1988) Cell survival and recovery processes in Chinese hamster AA8 cells and in two radiosensitive clones. Radiat Res 115:223-37
Murray, D; Meyn, R E; Vanankeren, S C (1988) Variations in the spectrum of lesions produced in the DNA of cells from mouse tissues after exposure to gamma-rays in air-breathing or in artificially anoxic animals. Int J Radiat Biol Relat Stud Phys Chem Med 53:921-33
Murray, D; Meyn, R E (1987) Differential repair of gamma-ray-induced DNA strand breaks by various cellular subpopulations of mouse jejunal epithelium and bone marrow in vivo. Radiat Res 109:153-64
Murray, D; vanAnkeren, S C; Meyn, R E (1987) Applicability of the alkaline elution procedure as modified for the measurement of DNA damage and its repair in nonradioactively labeled cells. Anal Biochem 160:149-59
Cantoni, O; Murray, D; Meyn, R E (1987) Induction and repair of DNA single-strand breaks in EM9 mutant CHO cells treated with hydrogen peroxide. Chem Biol Interact 63:29-38

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