The aims of this proposal are to: (1) test the hypothesis that radiation-induced division delay is not caused by damage to DNA, but is caused by damage to a non-DNA structure(s) associated with DNA at specific times in the cell cycle; (2) determine the cell cycle time of association; and (3) establish the relationship between damage to this non-DNA structure (i.e., division delay) and cell mortality. To accomplish these aims, Chinese hamster ovary (CHO) cells will be pulse labeled with 125-IUdR so that 125-I decays will irradiate DNA and its closely associated structures, but only inhibit cell progression in a portion of the labeled cells. 125-I decays will be specifically accumulated at various times in the cell cycle, by cooling to prevent progression. To avoid dependence on a single technique, two methods will be used to measure the effect of differential, cell cycle accumulation of 125-I decays on division delay: (1) 125-IUdR labeled cells will be selected in mitosis and decays accumulated at points throughout the cell cycle; (2) after 125-IUdR labeling, decays will be accumulated while the cells are either only in S- or in S- plus G2-phases, before they reach the first mitosis. In each case, the effect 125-I decays on cell entry into the subsequent mitosis will be assessed by comparing the time and rate of entry with and without accumulation of decays. The cell cycle association between DNA and the division delay structure can also be determined from these results; accumulation of 125-I decays will only affect cell progression at the times that the DNA and the non-DNA structure are associated. The relationship between 125-I-induced division delay and cell mortality will be based on the differences between the survival curves of the delayed and non-delayed populations. The long range goals of this research is to use the ability to separate 125-I-induced division delayed and non-delayed cells to identify and then study a cell-survival-related, non-DNA structure. Ultimately, identification of this structure could lead to new approaches to cancer therapy that depend, in part, on interaction with a non-DNA target.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Radiation Study Section (RAD)
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Florida State University
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Tauer, T J; Schneiderman, M H; Vishwanatha, J K et al. (1996) DNA double-strand break repair functions defend against parvovirus infection. J Virol 70:6446-9
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
Schneiderman, M H; Schneiderman, G S (1996) Radioiododeoxyuridine in cancer therapy: an in vitro approach to developing in vivo strategies. J Nucl Med 37:6S-9S
Charlton, D E; Hofer, K G; Vanloon, N et al. (1994) Double-strand breaks from 125I incorporated in the DNA and cell death. Int J Radiat Biol 66:437-40
Hofer, K G; van Loon, N; Schneiderman, M H et al. (1993) Targets for radiation-induced cell death: target replication during the cell cycle evaluated in cells exposed to X-rays or 125I decays. Int J Radiat Biol 64:205-16
Chiang, Y; Schneiderman, M H; Vishwanatha, J K (1993) Annexin II expression is regulated during mammalian cell cycle. Cancer Res 53:6017-21
Hofer, K G; van Loon, N; Schneiderman, M H et al. (1992) The paradoxical nature of DNA damage and cell death induced by 125I decay. Radiat Res 130:121-4
Harris, M E; Bohni, R; Schneiderman, M H et al. (1991) Regulation of histone mRNA in the unperturbed cell cycle: evidence suggesting control at two posttranscriptional steps. Mol Cell Biol 11:2416-24
Schneiderman, M H; Hofer, K G; Schneiderman, G S (1991) An in vitro 125IUdR-release assay for measuring the kinetics of cell death. Int J Radiat Biol 59:397-408
Schneiderman, M H; Hofer, K G; Schneiderman, G S (1990) Association between the division delay target and DNA late in the cell cycle. Radiat Res 122:337-40

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