The broad objective of this research is to better understand processes involved in the induction of chromosomal aberrations by ionizing radiation to help identify promising avenues of approach for future studies of molecular mechanisms. Perhaps more importantly, since various particular chromosomal translocations are required for many cancers, the project should shed some light on the question of radiation thresholds for cancer induction which is a key issue for radiation protection standards. The focus is on the dependence of RBE on the microscopic distributions of energy deposition in normal human cells where these energy deposition patterns can be manipulated to test specific hypotheses about the nature of aberration formation. The first hypothesis is that most exchange aberrations develop as a result of a damaged region of DNA interacting with an undamaged region (e.g., a recombinational misrepair?), as opposed to an alternative hypothesis involving interaction (misrejoining) of two damaged regions in close proximity. This would be studied by comparing the induction of exchange aberrations after exposing cells to 5 MeV alpha particles with that from damage after decay of 125IUdR incorporated into DNA. The ionization density is similar for these two radiations (~ 6 KeV within a 50 nanometer diameter sphere), but the spacing between the densely ionizing spheres is different for the two radiations. For alpha particles, the spheres are packed closely together to produce densely ionizing tracks 50 microns or so in length; in contrast, the spheres produced by disintegrations of 125I are separated spatially. Therefore, if two damaged regions must be in close proximity for an exchange to occur, the alpha particles would produce more exchanges than 125I disintegrations that deliver the same dose to the nucleus as the alpha particles. On the other hand, if only one damaged region is required, the effectiveness of the two radiations should be approximately the same. The second hypothesis is that for sparsely ionizing radiations, the densely ionizing track ends produce virtually all of the biological effect. This is based on observations of RBEs of 2 to 3 for Al or C ultrasoft x-rays. The test would involve comparing aberration induction by 14CTdR incorporated into DNA relative to 3HTdR incorporated into DNA. For 3H (range ~0.45 microns) virtually all tracks would originate and terminate in the nucleus, but for 14C beta particles (range ~37 microns) almost none of the tracks would end in a cell nucleus. Therefore, if the hypothesis were correct, 14C particle tracks should have almost no biological effect, and for a given dose to the nucleus, incorporated 3HTdR should be much more effective than incorporated 14CTdR. Since some chromosomal translocations are prerequisite for many cancers, basic knowledge of how chromosomal translocations are formed by radiation should help to better understand the hazards of radiation exposure as well as basic processes involved in oncogenesis. In a practical sense, the results of this study would be directly relevant to the question of thresholds for radiation oncogenesis.
| Bedford, Joel S; Liber, Howard L (2003) Applications of RNA interference for studies in DNA damage processing, genome stability, mutagenesis, and cancer. Semin Cancer Biol 13:301-8 |
| Dugan, Lawrence C; Bedford, Joel S (2003) Are chromosomal instabilities induced by exposure of cultured normal human cells to low- or high-LET radiation? Radiat Res 159:301-11 |
| Bedford, Joel S; Dewey, William C (2002) Radiation Research Society. 1952-2002. Historical and current highlights in radiation biology: has anything important been learned by irradiating cells? Radiat Res 158:251-91 |
