) 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.
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