The long term goal of this research program is to gain knowledge about mechanisms which determine the radiosensitivity of mammalian cells, with particular reference to those involved in the response of stationary or very slowly proliferating cell populations to x-irradiation. The approach is a multi-faceted one, and the endpoints to be investigated include mutagenesis, malignant transformation, cell survival and the induction of DNA damage and chromosomal abnormalities. This investigation will utilize primarily human diploid cells. An ultimate objective is to gain a better understanding of the molecular basis for the various cellular effects of radiation, as such knowledge should eventually allow a more rational approach to the prevention and treatment of human cancer. A particular focus of this project is on molecular and cellular processes associated with the repair of potentially lethal damage (PLDR) in cells x-irradiated during the stationary phase of growth. The inhibition of PLDR by chemical agents such as poly-ADP-ribose inhibitors and cordycepin will be investigated in an attempt to identify agents which might be useful clinically in the treatment of human tumors with a large capacity for PLDR. The modulating effect of PLDR on mutagenesis and sister chromatid exchanges (SCE) will be studied in cells from several genetic disorders characterized by hypersensitivity to radiation in vitro including xeroderma pigmentosum and Gardner's syndrome. The effect of PLDR on the progression of x-irradiated human cells through the life cycle after release from density-inhibition of growth will be studied in normal and ataxia telangiectasia homozygotes and heterozygotes. The dose-response relationships for the induction of mutations by x-rays will be investigated in cells from several hypersensitive genetic disorders utilizing the human diploid lymphoblast and skin fibroblast mutation assays. Finally, evidence will be sought for x-ray induced mitotic recombination in human diploid fibroblasts, and for the development of specific chromosomal rearrangements during the proliferation of irradiated cells in vitro. These will be correlated with the development of transformation to anchorage independent growth.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA011751-18
Application #
3163548
Study Section
Radiation Study Section (RAD)
Project Start
1979-04-01
Project End
1988-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
18
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Public Health
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Yandell, D W; Dryja, T P; Little, J B (1990) Molecular genetic analysis of recessive mutations at a heterozygous autosomal locus in human cells. Mutat Res 229:89-102
Little, J B; Dahlberg, W K (1989) Sensitization of noncycling human diploid cells to X-irradiation by pretreatment with 9-beta-D-arabinofuranosyladenine. Cancer Res 49:838-42
Nagasawa, H; Burke, M J; Little, F F et al. (1988) Multiple abnormalities in the ultraviolet light response of cultured fibroblasts derived from patients with the basal cell nevus syndrome. Teratog Carcinog Mutagen 8:25-33
Little, J B; Nove, J; Strong, L C et al. (1988) Survival of human diploid skin fibroblasts from normal individuals after X-irradiation. Int J Radiat Biol 54:899-910
Kano, Y; Grosovsky, A J; Little, J B (1987) Interrelationships among X-ray-induced anchorage independence, mutagenesis and chromosomal rearrangements in human diploid fibroblasts. Int J Cancer 40:64-8
Kelsey, K T; Nagasawa, H; Umans, R S et al. (1987) Epidermal growth factor induces cytogenetic damage in mammalian cells. Carcinogenesis 8:625-7
Nagasawa, H; Kraemer, K H; Shiloh, Y et al. (1987) Detection of ataxia telangiectasia heterozygous cell lines by postirradiation cumulative labeling index: measurements with coded samples. Cancer Res 47:398-402
Nove, J; Tarone, R E; Little, J B et al. (1987) Radiation sensitivity of fibroblast strains from patients with Usher's syndrome, Duchenne muscular dystrophy, and Huntington's disease. Mutat Res 184:29-38
Kano, Y; Little, J B (1986) Site-specific chromosomal rearrangements induced in human diploid cells by x-irradiation. Cytogenet Cell Genet 41:22-9
Krolewski, B; Nagasawa, H; Little, J B (1986) Effect of aliphatic amides on oncogenic transformation, sister chromatid exchanges, and mutations induced by cyclopenta[cd]-pyrene and benzo[a]pyrene. Carcinogenesis 7:1647-50

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