Comparison of RBE values of high-LET α-particles for the induction of DNA-DSBs, chromosome aberrations and cell reproductive death

Abstract

Background: Various types of radiation effects in mammalian cells have been studied with the aim to predict the radiosensitivity of tumours and normal tissues, e.g. DNA double strand breaks (DSB), chromosome aberrations and cell reproductive inactivation. However, variation in correlations with clinical results has reduced general application. An additional type of information is required for the increasing application of high-LET radiation in cancer therapy: the Relative Biological Effectiveness (RBE) for effects in tumours and normal tissues. Relevant information on RBE values might be derived from studies on cells in culture.

Methods: To evaluate relationships between DNA-DSB, chromosome aberrations and the clinically most relevant effect of cell reproductive death, for ionizing radiations of different LET, dose-effect relationships were determined for the induction of these effects in cultured SW-1573 cells irradiated with gamma-rays from a Cs-137 source or with α-particles from an Am-241 source. RBE values were derived for these effects. Ionizing radiation induced foci (IRIF) of DNA repair related proteins, indicative of DSB, were assessed by counting gamma-H2AX foci. Chromosome aberration frequencies were determined by scoring fragments and translocations using premature chromosome condensation. Cell survival was measured by colony formation assay. Analysis of dose-effect relations was based on the linear-quadratic model.

Results: Our results show that, although both investigated radiation types induce similar numbers of IRIF per absorbed dose, only a small fraction of the DSB induced by the low-LET gamma-rays result in chromosome rearrangements and cell reproductive death, while this fraction is considerably enhanced for the high-LET alpha-radiation. Calculated RBE values derived for the linear components of dose-effect relations for gamma-H2AX foci, cell reproductive death, chromosome fragments and colour junctions are 1.0 ± 0.3, 14.7 ± 5.1, 15.3 ± 5.9 and 13.3 ± 6.0 respectively.

Conclusions: These results indicate that RBE values for IRIF (DNA-DSB) induction provide little valid information on other biologically-relevant end points in cells exposed to high-LET radiations. Furthermore, the RBE values for the induction of the two types of chromosome aberrations are similar to those established for cell reproductive death. This suggests that assays of these aberrations might yield relevant information on the biological effectiveness in high-LET radiotherapy.

Figure 1

Number of γ-H2AX foci (A), Radiation dose survival curves (B), frequency of colour junctions (C) and chromosome fragments (D) for SW1573 cells after α particle (black squares) and gamma irradiation (black triangles). Calculated RBE values for DNA-DSBs, cell reproductive death, chromosome fragments and colour junctions are 1.0 ± 0.3, 14.7 ± 5.1, 15.3 ± 5.9 and 13.3 ± 6.0 resp.

Figure 2

Relative biological effectiveness (RBE) as a function of the linear energy transfer (LET) for different types of lethal damage in mammalian cells and for DNA damage. ILD, irrepairable lethal damage, derived as the contribution to the linear parameter α of the LQ model that is not repaired after irradiation of cells, even if maintained in conditions optimal for repair. PLD, potentially lethal damage, derived as the contribution to the linear parameter α that after irradiation is repaired in conditions optimal for repair. STLD, single track lethal damage, derived as the linear parameter α in conditions in which PLD is not repaired. SLD, sublethal damage, derived from survival curves as the square root of the quadratic parameter β of the LQ model. DNA-DSB, RBE for double strand breaks in DNA., DNA-SSB, RBE for single strand breaks in DNA. (from Barendsen et al.) [46].