Effects of Radiation Quality and Oxygen on Clustered DNA Lesions and Cell Death

Abstract

Radiation quality and cellular oxygen concentration have a substantial impact on DNA damage, reproductive cell death and, ultimately, the potential efficacy of radiation therapy for the treatment of cancer. To better understand and quantify the effects of radiation quality and oxygen on the induction of clustered DNA lesions, we have now extended the Monte Carlo Damage Simulation (MCDS) to account for reductions in the initial lesion yield arising from enhanced chemical repair of DNA radicals under hypoxic conditions. The kinetic energy range and types of particles considered in the MCDS have also been expanded to include charged particles up to and including (56)Fe ions. The induction of individual and clustered DNA lesions for arbitrary mixtures of different types of radiation can now be directly simulated. For low-linear energy transfer (LET) radiations, cells irradiated under normoxic conditions sustain about 2.9 times as many double-strand breaks (DSBs) as cells irradiated under anoxic conditions. New experiments performed by us demonstrate similar trends in the yields of non-DSB (Fpg and Endo III) clusters in HeLa cells irradiated by γ rays under aerobic and hypoxic conditions. The good agreement among measured and predicted DSBs, Fpg and Endo III cluster yields suggests that, for the first time, it may be possible to determine nucleotide-level maps of the multitude of different types of clustered DNA lesions formed in cells under reduced oxygen conditions. As particle LET increases, the MCDS predicts that the ratio of DSBs formed under normoxic to hypoxic conditions by the same type of radiation decreases monotonically toward unity. However, the relative biological effectiveness (RBE) of higher-LET radiations compared to (60)Co γ rays (0.24 keV/μm) tends to increase with decreasing oxygen concentration. The predicted RBE of a 1 MeV proton (26.9 keV/μm) relative to (60)Co γ rays for DSB induction increases from 1.9 to 2.3 as oxygen concentration decreases from 100% to 0%. For a 12 MeV (12)C ion (681 keV/μm), the 'predicted RBE for DSB induction increases from 3.4 (100% O(2)) to 9.8 (0% O(2)). Estimates of linear-quadratic (LQ) cell survival model parameters (α and β) are closely correlated to the Monte Carlo-predicted trends in DSB induction for a wide range of particle types, energies and oxygen concentrations. The analysis suggests α is, as a first approximation, proportional to the initial number of DSBs per cell, and β is proportional to the square of the initial number of DSBs per cell. Although the reported studies provide some evidence supporting the hypothesis that DSBs are a biologically critical form of clustered DNA lesion, the induction of Fpg and Endo III clusters in HeLa cells irradiated by γ rays exhibits similar trends with oxygen concentration. Other types of non-DSB cluster may still play an important role in reproductive cell death. The MCDS captures many of the essential trends in the formation of clustered DNA lesions by ionizing radiation and provides useful information to probe the mu...

Mechanisms of resistance to high and low linear energy transfer radiation in myeloid leukemia cells

“…36 Indeed, low LET irradiation under hypoxia almost eliminated radioresistance in RA5 and RG2 cells, whereas resistance to the clustered damage-inducing radiomimetics bleomycin and neocarzinostatin was modest in RA5 and RG2 cells, further supporting the hypothesis that DNA lesion type largely determines cell fate after IR exposure, even in cells technically defined as "radioresistant." 37 From a mechanistic standpoint, the changes in the cell survival curve after IR exposure in RA5 and RG2 cells could simply be attributed to reductions in IR-induced apoptosis, often observed in ␥-IR-resistant cancer cell variants, including HL60. [38][39][40] Similarly, the increased propensity to undergo mitosis in the radioresistant cells after IR exposure could account for radioresistance, despite residual chromosomal damage, as reported by other studies 41 (and J. Seideman, N. Veomett, D.A.S., observations under review, September 2009).…”

The effect of energy spectrum change on DNA damage in and out of field in 10-MV clinical photon beams

“…Using these electron spectra, the DSB induction per Gray per gigabase pair (Gy −1 Gbp −1 ) was calculated. MCDS parameters were tuned to obtain the minimum difference with measurements and track structure simulations [16,18,29]. MCDS uses typical mammalian cell for DNA damage calculations with including oxygen and chemical fixation [24].…”

“…Most MC microdosimetry codes use a simple DNA model that can be used to analyze the effect of different types of radiation to determine a link between the RBE of low-and high-linear energy transfer radiation [3,8,14,15,17,25,26,29]. The use of the condensed history track method in macrodosimetric MC for electron transport reduces simulation time when compared to microdosimetric MC codes that track particle transportation event by event.…”

“…This code has been developed to calculate the DNA damage of any mixtures of charged particles with different kinetic energies. This code can also calculate oxygen concentration effect on DNA damage [28,29].…”

Role of oxidatively-induced DNA damage and inflammation in radiation long term effects and carcinogenesis

“…a dense synthesis of DNA lesions are poorly repaired and expected to produce mutagenic effects and pro-malignant sites through chromosomal instability in cells and tissues (cancer precursor sites). Therefore, there is a critical need to delineate the molecular mechanisms behind the processing (repair) of radiation-induced clustered DNA damage and radiation effects [2] . In addition, it is of high importance to develop reliable radiation biomarkers that will predict the acute and/or delayed injury to specific organs and tissues after radiation exposure (radiation therapy) and methodologies to assay those biomarkers, to facilitate precise and timely medical interventions and optimization of radiation therapy [3] .…”