LET-dependence of lesion clustering in irradiated DNA

Full text: Irradiated DNA may suffer from several lesions, such as strand breaks and base damages. Isolated damage is in most cases correctly repaired by the cellular repair system. Clustered damage is more difficult to repair and can be lethal. Simulations and experiences have shown that the degree of clustering is LET-dependent. We present here the first-ever correlated results of biological and physical measurements of the clustering of radiation damage at the nanometer level. We compare physical data of ionization clusters within a gas model of DNA to biological data, measured by irradiating thin films of plasmid DNA (in-vitro) and quantifying the strand-break and base-damage clustering. The results of these studies, and nanotech with charged particles and gamma rays indicate a strong correlation between clustered ionization and clustered DNA damage. Our results show that the clustering of damage increases with LET as indicated by the increase in the yield of complex DSBs (per unit dose) with increasing LET. Furthermore, it is demonstrated that protons and He nuclei, both having the same LET value (25.5 keV/um in water), yield significantly different effects. The physical measurements reflect an increase in the frequency of large ionization clusters induced by protons compared to He nuclei; it is clearly attributed, by model simulations, to the different range of delta-electrons, leading to a more compact proton track structure. The biological measurements reflect twice as frequent proton-induced clustered lesions compared to irradiation by He nuclei. This work was supported by USPHS grant CA46295 and the NMTB under the U.S. Army Medical Research Acquisition Activity DAMD17-97-2-7016. The views and conclusions contained in this presentation are those of the authors and do not necessarily reflect the position or the policy of the U.S. Army or NMTB