) The conversion of a normal human cell to a cancer cell requires a series of steps, involving mutations conferring immortality, a growth advantage, and invasive ability. At 10-6 to 10-5 per generation, the mutation rate is too low to account for the occurrence of all of the necessary mutations for the carcinogenic process in the life time of a single cell or its progeny. Thus it has been hypothesized that a key early step in the carcinogenic process is the induction of genomic instability. The carcinogenic risks associated with the high Z radiation exposures experienced by space travelers could be amplified by the high efficiency with which high LET radiation exposures induce genomic instability. The identity of the target for inducing genomic instability and the mechanism for sustaining the instability phenotype, especially following exposure to high Z particles, are unknown. Preliminary studies by the applicant in a diploid human B-lymphoblastoid cell line suggest that there may be more than one mechanism underlying the induction of genomic instability and that, therefore, there may be more than one target for its induction. To investigate this hypothesis, she plans to examine the frequency and types of instability that develop in TK6 human lymphoblastoid cells following exposure to 1 GeV/nucleon iron particles generated at Brookhaven National Laboratories as compared to similar cultures exposed to low LET radiation and to unirradiated control cultures. Unstable clones will be identified by variation in their progeny with regard to (1) large scale cytogenetic changes, (2) the occurrence of delayed gene mutations, and (3) a delayed decrease in plating efficiency. Once identified, unstable clones will be further characterized to determine the basis of the induced genomic instability. Characteristics to be measured include the spectra of chromosomal aberrations and gene mutations, the presence of cell cycle regulation, and the level of recombinational activity. Knowledge of the target for the induction of instability and the nature of that instability is important for the development of better predictive models of risk and appropriate radiation protection measures.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073931-02
Application #
2683698
Study Section
Special Emphasis Panel (ZCA1-CRB-X (J1))
Program Officer
Pelroy, Richard
Project Start
1997-09-30
Project End
2001-09-30
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Schwartz, Jeffrey L; Jordan, Robert; Evans, Helen H et al. (2004) Baseline levels of chromosome instability in the human lymphoblastoid cell TK6. Mutagenesis 19:477-82
Evans, Helen H; Horng, Min-Fen; Ricanati, Marlene et al. (2003) Induction of genomic instability in TK6 human lymphoblasts exposed to 137Cs gamma radiation: comparison to the induction by exposure to accelerated 56Fe particles. Radiat Res 159:737-47
Schwartz, Jeffrey L; Jordan, Robert; Evans, Helen H et al. (2003) The TP53 dependence of radiation-induced chromosome instability in human lymphoblastoid cells. Radiat Res 159:730-6
Evans, H H; Evans, T E; Horng, M F (2002) Antimutagenicity of WR-1065 in L5178Y cells exposed to accelerated (56)Fe ions. Radiat Res 158:110-4
Evans, Helen H; Horng, Min-Fen; Ricanati, Marlene et al. (2002) Characteristics of genomic instability in clones of TK6 human lymphoblasts surviving exposure to 56Fe ions. Radiat Res 158:687-98
Evans, H H; Horng, M F; Ricanati, M et al. (2001) Diverse delayed effects in human lymphoblastoid cells surviving exposure to high-LET (56)Fe particles or low-LET (137)Cs gamma radiation. Radiat Res 156:259-71
Schwartz, J L; Jordan, R; Liber, H et al. (2001) TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines. Genes Chromosomes Cancer 30:236-44
Schwartz, J L; Jordan, R; Evans, H H (2001) Characteristics of chromosome instability in the human lymphoblast cell line WTK1. Cancer Genet Cytogenet 129:124-30
Limoli, C L; Corcoran, J J; Jordan, R et al. (2001) A role for chromosomal instability in the development of and selection for radioresistant cell variants. Br J Cancer 84:489-92
Evans, H H; Horng, M F; Evans, T E et al. (2001) Genotoxic effects of high-energy iron particles in human lymphoblasts differing in radiation sensitivity. Radiat Res 156:186-94

Showing the most recent 10 out of 13 publications