Genomic Maintenance & Repair

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP336) Interindividual variation in genomic instability after targeted charged particle microbeam irradiation.

Moore, Stephen*,1, Folkard, Melvyn2, Prise, Kevin2, Kadhim, Munira1, 1 Radiation and Genome Stability Unit, Harwell, Oxfordshire, United Kingdom2 Gray Cancer Institute, Northwood, Middlesex, United Kingdom

ABSTRACT- Genomic instability, a hallmark of tumorigenic progression, is observed in a fraction of the progeny of cells surviving ionizing radiation. Environmental exposure to high LET radiation such as radon and its daughters generally results in very few cells in the population being traversed, particularly more than once. Individual variation in response may be an important consideration under such conditions. Using the Gray Cancer Institute charged particle microbeam (3He2+ particles; 105 KeV/m) and primary lymphocytes from a single donor, we reported that instability is similarly induced when fractions of the populations (n 1000 cells) down to a single cell were targeted for traversal by a single 3He2+ ion (Moore et al. Radiat Res. 2005, 163: 183-190). To assess genetic predisposition to genomic instability, replicate experiments were performed with additional donors. Two of the donors showed the same general trend of instability induction as Moore et al. (2005), but with differences in background and magnitude of instability induction. In one donor, instability was not significantly induced. Furthermore, because our initial studies indicated involvement of TNF- in the initiation of instability, we sampled supernatants, performed ELISA on a panel of pro-inflammatory cytokines, and found substantial variation between donors and between treatments. Experiments are underway using SELDI-TOF mass spectrometry to measure TNF- (and TGF-) levels before and after antibody-based inactivation; instability will be assessed with and without cytokine inactivation under all irradiation conditions. Finally, we observed substantial inter-experimental variation when a single cell was irradiated (as in Moore et al. 2005), possibly due to intercellular differences in generating a bystander signal, and experiments to this characterize variation are ongoing. These experiments will contribute to our understanding of the induction of instability in irradiated and bystander cells under environmentally relevant doses of high LET radiation, and may impact risk assessment based on inter-individual variation.

Key words: genomic instability, genetic predisposition, bystander effects, microbeam

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2005 RRS