High Linear Energy Transfer Radiation Research Articles

Comparison on the Biological Effects of Low and High Linear Energy Transfer Radiation and to Calculate Its Relative Biological Effects in Direct and Bystander Cells

Comparison on the Biological Effects of Low and High Linear Energy Transfer Radiation and to Calculate Its Relative Biological Effects in Direct and Bystander Cells

Cytogenetic Biomarkers of Radiation Exposure

Biological monitoring of radiation exposure relies heavily on the quantification of chromosome aberrations such as dicentrics and reciprocal translocations in the peripheral blood lymphocytes of exposed and potentially exposed subjects. The differences in the spatial deposition of energy and the quality of damage initially induced between individual low- and high-linear energy transfer (LET) radiation tracks are known to impact dramatically on the type and complexity of chromosome aberration induced. Over the years, researchers have proposed numerous cytogenetic markers and signatures based on these differences with the aim of biologically discriminating exposure to radiation of varying qualities. Complex chromosome aberrations are a broad classification of aberration types that are known to be characteristically induced after low doses of high-LET. The mechanistic basis for complex aberration formation and the potential applicability of these complex aberration products as LET-specific biomarkers are considered.

Characterisation of Deubiquitylating Enzymes in the Cellular Response to High-LET Ionizing Radiation and Complex DNA Damage

PurposeIonizing radiation, particular high-linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) wherein 2 or more DNA lesions are induced in close proximity, which contributes significantly to the cell killing effects. However, knowledge of the enzymes and mechanisms involved in coordinating the recognition and processing of CDD in cellular DNA are currently lacking.Methods and MaterialsA small interfering RNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET α-particles or protons, versus low-LET protons and x-rays, and cell survival was monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed using an enzyme modified neutral comet assay.ResultsDepletion of USP6 decreased cell survival specifically after high-LET α-particles and protons, but not low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1) protein. Increased radiosensitivity of cells to high-LET protons as a consequence of defective CDD repair was furthermore mimicked using the PARP inhibitor olaparib, and through PARP-1 small interfering RNA.ConclusionsUSP6 controls cell survival in response to high-LET radiation by stabilizing PARP-1 protein levels, which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition, or PARP-1 depletion, in effective cancer cell killing.

Novel Neuromorphic Computing based Monte Carlo Simulation of Alpha Particles Penetration into Tumor Cells in Targeted Alpha Therapy

Recent breakthrough of radiotherapy to cancers focuses on the high linear energy transfer (LET) radiation, e.g., the alpha particles. Targeted Alpha Therapy (TAT) is an important option of radiotherapeutic method for the treatment of cancers. TAT uses an alpha-immunoconjugate (AIC) comprising a tumor selective molecule, which attaches to the surface of specific tumor cells selectively and then undergoes alpha decay to destroy the tumor cells. Monte Carlo (MC) calculations are a well-suited method to accurately simulate the energy deposited by ionizing radiation in very small biological structures such as DNA. Thus, MC simulation is the essential technology to estimate Alpha particles penetration into tumors and to accurately determine the optimum therapeutic dose of TAT. However, the computation complexity of MC in the TAT scenario is extremely expensive and then it is impractical to estimate the optimum therapeutic dose under the clinical setting. Consequently, it is very necessary to explore a highly effective computation solution to make alpha particle penetration simulation practical for TAT. MC method is usually based on massive parallel computing, and neuromorphic computing based solution is a promising solution to achieve large speed-up of computing effectiveness for the MC simulation. By simply mimicking computing mechanism of human brain, the neuromorphic computing architecture achieves optimal computing efficiency by integrating memory and processing units on a single chip and has been extensively applied in artificial intelligence (AI) application acceleration. In this work, our developed neuromorphic engine with employing novel nano-device (e.g. memristor) for highly enhanced computing parallelism is applied in the MC simulation. Basic computation models in the MC simulation such as Bayesian network is computed by the proposed neuromorphic engine. Improved neuromorphic design is further developed in algorithm and hardware to fit the computations in the MC simulation of the TAT. The simulation results of alpha particles penetration into tumor cells of TAT with highly improved computing speed and energy are presented.

Neutron-induced Rat Mammary Carcinomas Are Mainly of Luminal Subtype and Have Multiple Copy Number Aberrations.

Neutrons are used as a type of high linear energy transfer (LET) radiation and they have stronger carcinogenic effects compared to low LET radiation. We sought to clarify the features of mammary carcinomas for which the incidence increases when these were exposed to neutron radiation. We compared mammary carcinomas from female Sprague-Dawley rats irradiated at 7 weeks of age with 0.485 Gy neutron beams or 0.5-Gy γ rays, with carcinomas of non-irradiated rats. Tumors were classified into luminal and non-luminal subtypes based on immunohistochemistry, while their copy number aberrations were determined using microarrays. Neutrons and γ rays significantly increased the incidence of luminal carcinomas. The carcinomas in the three groups contained multiple aberrations affecting 46 genes for which mutations have been reported in human breast cancer. Neutrons and γ rays increase the incidence of luminal mammary carcinoma in rats, probably via genetic aberrations similar to those found in human breast cancer patients.

Abstract P3-12-21: Development of peptide-based targeted α-therapy for triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is associated with a poorer prognosis, including a higher potential to metastasize and a decrease in the 5-year survival rate as compared to other breast cancer subtypes (77% vs. 93%). The poor prognosis is partially due to the lack of targeted treatments for TNBC, highlighting the need to develop targeted therapies for TNBC. Alpha-emitting radionuclides, such as Actinium-225, provide high linear energy transfer (LET) radiation. Clinical and pre-clinical studies have shown that targeted alpha-therapy is a highly potent treatment for metastatic cancer. Peptides and peptidomimetics are minimally immunogenic and have rapid tissue and tumor penetration, and rapid clearance from non-target tissues, providing an attractive platform for targeted therapeutic agent. The RGD peptide has been shown to have a high affinity for αvβ3, which has been implicated in TNBC. The purpose of these studies is to investigate the potential of modified RGD peptide scaffolds to deliver 225Ac to triple negative breast cancer cells for targeted alpha therapy. Methods DOTA-cyclo-RGD(fK) and DOTA-cyclo-RGD(fK) dimer were labeled with Indium-111, a SPECT imaging surrogate for 225Ac, and Actinium-225. The resulting labeled agents were evaluated in vitro, including binding affinity assays (111In) and colony formation assays (225Ac) that are underway using the MDA-MB-231 cell line. Biodistribution experiments were performed in athymic nude mice bearing MDA-MB-231 tumors to compare the distribution and pharmacokinetics of the 111In-labeled RGD peptide scaffolds in vivo. Alpha camera imaging evaluated the microscale distribution of 225Ac-DOTA-cyclo-RGD(fK) in non-tumor bearing mice. Results The saturation binding assay of 111In-labeled DOTA-cyclo-RGD(fK) and DOTA-cyclo-RGD(fK) dimer demonstrated selective binding and nanomolar affinity for αvβ3. Selective targeting of αvβ3was further demonstrated in vivo for both 111In-labeled RGD agents. The 111In-labeled DOTA-cyclo-RGD(fK) demonstrated significantly higher tumor uptake at 30 minutes compared to the dimer (5.3 ± 2.9 vs. 3.0 ± 1.4 %ID/g). The 111In-DOTA-cyclo-RGD(fK) dimer was better retained in the tumor over 6 hours with significantly higher uptake at the 6-hour time point (1.2 ± 0.4 vs. 2.8 ± 1.1 %ID/g). Furthermore, the dimer had significantly higher uptake in the kidney and liver over a 6-hour window as compared to 111In-DOTA-cyclo-RGD(fK). However, both 111In-labeled RGD agents demonstrated rapid clearance from normal organs. Alpha camera images of the 225Ac-labeled dimer supported the rapid clearance from the normal tissues, with the majority of the agents being cleared within the first 90 minutes. Conclusion Modified RGD peptides were successfully labeled with Indium-111 and Actinium-225. The resulting agents were shown to successfully target αvβ3 selectively both in vitro and in vivo. These studies provide encouraging data to support the development and optimization of the RGD platform for αvβ3-targeted alpha therapy to treat triple negative breast cancer. Future works will investigate the therapeutic efficacy, macro- and microscale dosimetry, and toxicity of the developed 225Ac-labeled αvβ3-targeted agents as well as explore the optimization of the RGD scaffold for improved pharmacokinetics with 225Ac. Citation Format: Nedrow JR, Cortez A, Josefsson A, Sgouros G. Development of peptide-based targeted α-therapy for triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-21.

Biological outcomes of γ-radiation induced DNA damages in breast and lung cancer cells pretreated with free radical scavengers

Purpose: Investigation of effects on DNA of γ-irradiated human cancer cells pretreated with free radical scavengers is aimed to create reference data which would enable assessment of the relative efficiency of high linear energy transfer (LET) radiations used in hadron therapy, i.e. protons and carbon ions.Materials and methods: MCF-7 breast and HTB177 lung cancer cells are irradiated with γ-rays. To minimize indirect effects of irradiation, dimethyl sulfoxide (DMSO) or glycerol are applied as free radical scavengers. Biological response to irradiation is evaluated through clonogenic cell survival, immunocytochemical and cell cycle analysis, as well as expression of proteins involved in DNA damage response.Results: Examined cell lines reveal similar level of radioresistance. Application of scavengers leads to the rise of cell survival and decreases the number of DNA double strand breaks in irradiated cells. Differences in cell cycle and protein expression between the two cell lines are probably caused by different DNA damage repair mechanisms that are activated.Conclusion: The obtained results show that DMSO and glycerol have good scavenging capacity, and may be used to minimize DNA damage induced by free radicals. Therefore, they will be used as the reference for comparison with high LET irradiations, as well as good experimental data suitable for validation of numerical simulations.

Hyperthermia: The Optimal Treatment to Overcome Radiation Resistant Hypoxia.

Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39–45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.

Hyperthermia with photon radiotherapy is thermoradiobiologically analogous to neutrons for tumors without enhanced normal tissue toxicity

The depth dose profiles of photons mirror those of fast neutrons. However, in contrast to the high linear energy transfer (LET) characteristics of neutrons; photons exhibit low LET features. Hyperthermia (HT) inhibits the repair of radiation-induced DNA damage and is cytotoxic to the radioresistant hypoxic tumor cells. Thus, thermoradiobiologically, HT simulates high LET radiation with photons. At temperatures of 39–45 °C, the physiological vasodilation allows rapid heat dissipation from normal tissues. On the contrary, the chaotic and relatively rigid tumor vasculature results in heat retention leading to higher intratumoural temperatures. Consequently, the high LET attributes of HT with photon radiations are mostly limited to the confines of the heated tumor while the normothermic normal tissues would be irradiated with low LET photons. HT thereby augments photon therapy by conferring therapeutic advantages of high LET radiations to the tumors akin to neutrons, while the ‘heat-sink’ effect spares the normal tissues from thermal radiosensitization. Thus, photon thermoradiotherapy imparts radiobiological advantages selectively to tumors analogous to neutrons without exaggerating normal tissue morbidities. The later has been the major concern with clinical fast neutron beam therapy. Outcomes reported from several clinical trials in diverse tumor sites add testimony to the enhanced therapeutic efficacy of photon thermoradiotherapy.

Radiolytic Degradation of Uranyl-Loaded Tributyl Phosphate by High and Low LET Radiation

ABSTRACT Understanding and characterizing the radiolytic degradation of solvents used for treatment of used nuclear fuel is an ongoing topic of research. In the work presented here, degradation constants for the radiolysis of tributyl phosphate (TBP) as a function of various process variables, such as the inclusion of nitric acid and uranyl ions on the TBP, were determined. Degradation constants were determined for both high linear energy transfer (LET) and low LET (gamma) radiation exposure. Results indicate that susceptibility to gamma radiolysis is roughly twice that of high LET and that acid uptake by TBP has little effect on the overall degradation for both high and low LET irradiations. The inclusion of a metal ion affects the degradation of TBP by forming complexes that absorb a portion of the energy deposited by radiation. These TBP–metal complexes break down during irradiation, and the degradation constants for the complex were found to be higher compared to free TBP, for both high and low LET radiations suggesting that the TBP–uranyl complex is more susceptible to radiation than free TBP.

NON-TARGETED EFFECTS LEAD TO A PARIDIGM SHIFT IN RISK ASSESSMENT FOR A MISSION TO THE EARTH'S MOON OR MARTIAN MOON PHOBOS.

Cancer risk is an important limitation for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Many studies suggest non-targeted effects (NTEs) occur for low doses of high-linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. We investigate corrections to quality factors (QF) for NTEs, which are used in predictions of fatal cancer risks for exploration missions. Prediction of fatal cancer risks for missions to the Martian moon, Phobos of 500-d and the Earth's moon of 365-d for average solar minimum condition show increases of 2- to 4-fold higher in the NTE model compared with the conventional model. Limitations in estimating uncertainties in NTE model parameters due to sparse radiobiology data at low doses are discussed.

DEFINED BIOLOGICAL MODELS OF HIGH-LET RADIATION LESIONS.

DNA double-strand break (DSB) complexity is invoked to explain the increased efficacy of high-linear energy transfer (LET) radiation. Complexity is usually defined as presence of additional lesions in the immediate proximity of the DSB. DSB-clusters represent a different level of complexity that can jeopardize processing by destabilizing chromatin in the vicinity of the cluster. DSB-clusters are generated after exposure of cells to ionizing radiation (IR), particularly high-LET radiation, and have been considered as particularly consequential in several mathematical models of IR action. Yet, experimental demonstration of their relevance to the adverse IR effects, as well as information on the mechanisms underpinning their severity as DNA lesions is lacking. We addressed this void by developing cell lines with especially designed, multiply integrated constructs modeling defined combinations of DSB-clusters through appropriately engineered I-SceI meganuclease recognition sites. Using this model system, we demonstrate efficient activation of the DNA damage response, as well as a markedly increased potential of DSB-clusters, as compared to single-DSBs, to kill cells, and cause Parp1- dependent chromosomal translocations. We propose that DSB repair relying on first line DSB-processing pathways (canonical non-homologous end joining and to some degree homologous recombination repair) is compromised within DSB clusters, presumably through the associated chromatin destabilization, leaving alternative end joining as last option and translocation formation as a natural consequence. Our observations offer a mechanistic explanation for the increased efficacy of high-LET radiation.

Single-molecule localization microscopy as a promising tool for γH2AX/53BP1 foci exploration

Quantification and structural studies of DNA double strand breaks (DSBs) are an essential part of radiobiology because DSBs represent the most serious damage introduced to the DNA molecule by ionizing radiation. Although standard immunofluorescence confocal microscopy has demonstrated its usefulness in a large number of research studies, it lacks the resolution required to separate individual, closely associated DSBs, which appear after cell exposure to high linear energy transfer (high-LET) radiation and can be visualized as clusters or streaks of radiation-induced repair foci (IRIFs). This prevents our deeper understanding of DSB induction and repair. Recent breakthroughs in super-resolution light microscopy, such as the development of single-molecule localization microscopy (SMLM), offer an optical resolution of approximately an order of magnitude better than that of standard confocal microscopy and open new horizons in radiobiological research. Unlike electron microscopy, SMLM (also referred to as “nanoscopy”) preserves the natural structure of biological samples and is not limited to very thin sample slices. Importantly, SMLM not only offers a resolution on the order of approximately 10 nm, but it also provides entirely new information on the biochemistry and spatio-temporal organization of DSBs and DSB repair at the molecular level. Nevertheless, it is still challenging to correctly interpret these often surprising nanoscopy results. In the present article, we describe our first attempts to use SMLM to explore γH2AX and 53BP1 repair foci induced with 15N high-LET particles.

Morphological Analysis of Amoeboid–Mesenchymal Transition Plasticity After Low and High LET Radiation on Migrating and Invading Pancreatic Cancer Cells

Cell migration and invasion are fundamental components of tumor cell metastasis that represent the biggest threat to the survival and quality of life of cancer patients. There is clear evidence that ionizing radiation can differently modulate migration and invasiveness of cancer cells depending on the cell lines, the doses and the radiation types investigated. This suggests that motile cells are able to adopt different migration strategies according to their molecular characteristics and external signals. In this study, a morphological analysis was performed on pancreatic cancer Aspc-1 cells to evaluate the amoeboid-mesenchymal mobility transition in several experimental conditions considering the role played by factors released by normal and tumor cells, in basal conditions and after low and high Linear Energy Transfer (LET) irradiation. The migratory behavior of Aspc-1 cells is modulated by factors released by normal fibroblasts and tumor cells, and this is in turn modulated by both the radiation dose and the radiation quality.

The Role of the Nuclear Factor κB Pathway in the Cellular Response to Low and High Linear Energy Transfer Radiation.

Astronauts are exposed to considerable doses of space radiation during long-term space missions. As complete shielding of the highly energetic particles is impracticable, the cellular response to space-relevant radiation qualities has to be understood in order to develop countermeasures and to reduce radiation risk uncertainties. The transcription factor Nuclear Factor κB (NF-κB) plays a fundamental role in the immune response and in the pathogenesis of many diseases. We have previously shown that heavy ions with a linear energy transfer (LET) of 100–300 keV/µm have a nine times higher potential to activate NF-κB compared to low-LET X-rays. Here, chemical inhibitor studies using human embryonic kidney cells (HEK) showed that the DNA damage sensor Ataxia telangiectasia mutated (ATM) and the proteasome were essential for NF-κB activation in response to X-rays and heavy ions. NF-κB’s role in cellular radiation response was determined by stable knock-down of the NF-κB subunit RelA. Transfection of a RelA short-hairpin RNA plasmid resulted in higher sensitivity towards X-rays, but not towards heavy ions. Reverse Transcriptase real-time quantitative PCR (RT-qPCR) showed that after exposure to X-rays and heavy ions, NF-κB predominantly upregulates genes involved in intercellular communication processes. This process is strictly NF-κB dependent as the response is completely absent in RelA knock-down cells. NF-κB’s role in the cellular radiation response depends on the radiation quality.

Role of High-Linear Energy Transfer Radiobiology in Space Radiation Exposure Risks.

Many manned missions to the Moon and Mars are scheduled in the near future. However, space radiation presents a major hazard to humans, and astronauts are constantly exposed to radiation, including high linear energy transfer (LET) radiation, which differs from radiation on Earth. Thus, there is thus an urgent need to clarify the biological effects of space radiation and reduce the associated risks. In this review, we consider the role of high-LET radiobiology in relation to space-radiation exposure.

Early effects of 16O radiation on neuronal morphology and cognition in a murine model

Astronauts exposed to high linear energy transfer radiation may experience cognitive injury. The pathogenesis of this injury is unknown but may involve glutamate receptors or modifications to dendritic structure and/or dendritic spine density and morphology. Glutamate is the major excitatory neurotransmitter in the central nervous system, where it acts on ionotropic and metabotropic glutamate receptors located at the presynaptic terminal and in the postsynaptic membrane at synapses in the hippocampus. Dendritic spines are sites of excitatory synaptic transmission, and changes in spine structure and dendrite morphology are thought to be morphological correlates of altered brain function associated with hippocampal-dependent learning and memory. The aim of the current study is to assess whether behavior, glutamate receptor gene expression, and dendritic structure in the hippocampus are altered in mice after early exposure to 16O radiation in mice. Two weeks post-irradiation, animals were tested for hippocampus-dependent cognitive performance in the Y-maze. During Y-maze testing, mice exposed to 0.1 Gy and 0.25 Gy radiation failed to distinguish the novel arm, spending approximately the same amount of time in all 3 arms during the retention trial. Exposure to 16O significantly reduced the expression of Nr1 and GluR1 in the hippocampus and modulated spine morphology in the dentate gyrus and cornu Ammon 1 within the hippocampus. The present data provide evidence that 16O radiation has early deleterious effects on mature neurons that are associated with hippocampal learning and memory.

Radiosensitization Effect of Talazoparib, a Parp Inhibitor, on Glioblastoma Stem Cells Exposed to Low and High Linear Energy Transfer Radiation

Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents. In this study, we investigated the preclinical efficacy of talazoparib, a new PARPi, in association with low and high linear energy transfer (LET) irradiation in two GSC cell lines. Reduction of GSC fraction, impact on cell proliferation, and cell cycle arrest were evaluated for each condition. All combinations were compared with a reference schedule: photonic irradiation combined with temozolomide. The use of PARPi combined with photon beam and even more carbon beam irradiation drastically reduced the GSC frequency of GBM cell lines in vitro. Furthermore, talazoparib combined with irradiation induced a marked and prolonged G2/M block, and decreased proliferation. These results show that talazoparib is a new candidate that effects radiosensitization in radioresistant GSCs, and its combination with high LET irradiation, is promising.

Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization

While many efforts have been made to pave the way toward human space colonization, little consideration has been given to the methods of protecting spacefarers against harsh cosmic and local radioactive environments and the high costs associated with protection from the deleterious physiological effects of exposure to high-Linear energy transfer (high-LET) radiation. Herein, we lay the foundations of a roadmap toward enhancing human radioresistance for the purposes of deep space colonization and exploration. We outline future research directions toward the goal of enhancing human radioresistance, including upregulation of endogenous repair and radioprotective mechanisms, possible leeways into gene therapy in order to enhance radioresistance via the translation of exogenous and engineered DNA repair and radioprotective mechanisms, the substitution of organic molecules with fortified isoforms, and methods of slowing metabolic activity while preserving cognitive function. We conclude by presenting the known associations between radioresistance and longevity, and articulating the position that enhancing human radioresistance is likely to extend the healthspan of human spacefarers as well.

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.