Induction of apoptosis by high linear energy transfer radiation: role of p53

2002 ◽  
Vol 80 (7) ◽  
pp. 644-649 ◽  
Author(s):  
D Coelho ◽  
B Fischer ◽  
V Holl ◽  
P Dufour ◽  
J M Denis ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Cell Line ◽  
Linear Energy Transfer ◽  
Lymphoblastoid Cell Line ◽  
Cellular Damage ◽  
Fast Neutrons ◽  
X Rays ◽  
Carbon Ions ◽  
High Let Radiation ◽  
High Let

The involvement of the tumor suppressor p53 gene in the sensitivity of many cell types towards low linear energy transfer (LET) radiation is now well established. However, little information is available on the relationship between p53 status of tumor cells and their ability to undergo apoptosis following exposure to high-LET radiation. Here we present the results of experiments carried out with the human lymphoblastoid cell line TK6 and its p53 knock-out counterpart NH32. Cells were irradiated at doses ranging from 0.25 to 8 Gy with fast neutrons (65 MeV), carbon ions (95 MeV/nucleon), and X rays (15 MV). For both cell lines, the occurrence of apoptosis, determined by the quantification of hypodiploid particles as well as the activation of several caspases, was compared with their sensitivity towards high-LET radiation. Results indicate that p53 is involved in the response of TK6 cells to fast neutrons and carbon ions, as measured by cell proliferation and occurrence of apoptosis. However, p53-deficient cells are still able to undergo apoptosis following irradiation. This suggests that heavy ions and fast neutrons induce cellular damage that is not under the control of p53. The involvement of executioner caspases in high-LET radiation induced apoptosis was also evaluated by use of specific inhibitors.Key words: fast neutrons, carbon ions, apoptosis, p53, lymphoblastoid cell line.

scholarly journals Dependence and independence of survival parameters on linear energy transfer in cells and tissues

2016 ◽  
Vol 57 (6) ◽  
pp. 596-606 ◽  
Author(s):  
Koichi Ando ◽  
Dudley T. Goodhead
Keyword(s):  
Energy Transfer ◽  
Linear Energy Transfer ◽  
Quadratic Model ◽  
X Rays ◽  
Linear Quadratic ◽  
Linear Quadratic Model ◽  
Mammalian Cell Lines ◽  
High Let Radiation ◽  
High Let

Abstract Carbon-ion radiotherapy has been used to treat more than 9000 cancer patients in the world since 1994. Spreading of the Bragg peak is necessary for carbon-ion radiotherapy, and is designed based on the linear–quadratic model that is commonly used for photon therapy. Our recent analysis using in vitro cell kills and in vivo mouse tissue reaction indicates that radiation quality affects mainly the alpha terms, but much less the beta terms, which raises the question of whether this is true in other biological systems. Survival parameters alpha and beta for 45 in vitro mammalian cell lines were obtained by colony formation after irradiation with carbon ions, fast neutrons and X-rays. Relationships between survival parameters and linear energy transfer (LET) below 100 keV/μm were obtained for 4 mammalian cell lines. Mouse skin reaction and tumor growth delay were measured after fractionated irradiation. The Fe-plot provided survival parameters of the tissue reactions. A clear separation between X-rays and high-LET radiation was observed for alpha values, but not for beta values. Alpha values/terms increased with increasing LET in any cells and tissues studied, while beta did not show a systematic change. We have found a puzzle or contradiction in common interpretations of the linear-quadratic model that causes us to question whether the model is appropriate for interpreting biological effectiveness of high-LET radiation up to 500 keV/μm, probably because of inconsistency in the concept of damage interaction. A repair saturation model proposed here was good enough to fit cell kill efficiency by radiation of wide-ranged LET. A model incorporating damage complexity and repair saturation would be suitable for heavy-ion radiotherapy.

Cisplatin enhances the cytotoxicity of fast neutrons in a murine lymphoma cell line

2004 ◽  
Vol 82 (2) ◽  
pp. 140-145 ◽  
Author(s):  
B Fischer ◽  
S Benzina ◽  
V Ganansia-Leymarie ◽  
J M Denis ◽  
J P Bergerat ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Cell Lymphoma ◽  
Fast Neutrons ◽  
Lymphoma Cell Line ◽  
Carbon Ions ◽  
Time Intervals ◽  
Proliferation And Apoptosis ◽  
High Let ◽  
High Linear Energy Transfer

The utilization of high linear energy transfer (LET) radiations, such as fast neutrons or carbon ions (hadrontherapy), offers promising perspectives in radiotherapy. While it is well known that by combining radiotherapy and chemotherapy, important therapeutic advantages can be obtained to cure cancer, there have been, so far, very few investigations on the effects of treatments combining an irradiation with high-LET particles and cancer drugs. The present study was therefore undertaken to examine the effects of exposure to 65 MeV fast neutrons combined with cisplatin in a murine T cell lymphoma (RDM4) in vitro. The cells were irradiated at doses ranging from 2 to 8 Gy without or with addition of cisplatin shortly before the irradiation, at concentrations between 0.3 and 12.5 µM. These treatments were applied concomitantly. Proliferation and apoptosis were assessed at different time intervals thereafter. The combination of irradiation with cisplatin was found to be more cytotoxic than either treatment alone. Furthermore, the cytotoxicity induced by this cotreatment resulted not only from apoptosis but also from other forms of cell death.Key words: apoptosis, cancer cells, fast neutrons, cisplatin.

scholarly journals Distinct Roles of Ape1 Protein, an Enzyme Involved in DNA Repair, in High or Low Linear Energy Transfer Ionizing Radiation-induced Cell Killing

2014 ◽  
Vol 289 (44) ◽  
pp. 30635-30644 ◽  
Author(s):  
Hongyan Wang ◽  
Xiang Wang ◽  
Guangnan Chen ◽  
Xiangming Zhang ◽  
Xiaobing Tang ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Linear Energy Transfer ◽  
Cell Killing ◽  
Dna Fragments ◽  
End Joining ◽  
Heavy Charged Particles ◽  
High Let Radiation ◽  
High Let ◽  
Radiation Induced ◽  
Non Homologous End Joining

High linear energy transfer (LET) radiation from space heavy charged particles or a heavier ion radiotherapy machine kills more cells than low LET radiation, mainly because high LET radiation-induced DNA damage is more difficult to repair. Relative biological effectiveness (RBE) is the ratio of the effects generated by high LET radiation to low LET radiation. Previously, our group and others demonstrated that the cell-killing RBE is involved in the interference of high LET radiation with non-homologous end joining but not homologous recombination repair. This effect is attributable, in part, to the small DNA fragments (≤40 bp) directly produced by high LET radiation, the size of which prevents Ku protein from efficiently binding to the two ends of one fragment at the same time, thereby reducing non-homologous end joining efficiency. Here we demonstrate that Ape1, an enzyme required for processing apurinic/apyrimidinic (known as abasic) sites, is also involved in the generation of small DNA fragments during the repair of high LET radiation-induced base damage, which contributes to the higher RBE of high LET radiation-induced cell killing. This discovery opens a new direction to develop approaches for either protecting astronauts from exposure to space radiation or benefiting cancer patients by sensitizing tumor cells to high LET radiotherapy.

High Linear Energy Transfer Degradation Studies Simulating Alpha Radiolysis of TRU Solvent Extraction Processes

2013 ◽  
Author(s):  
Jeremy Pearson ◽  
George Miller ◽  
Mikael Nilsson
Keyword(s):  
Energy Transfer ◽  
Solvent Extraction ◽  
Gamma Radiation ◽  
Nuclear Fuel ◽  
Linear Energy Transfer ◽  
Radioactive Isotopes ◽  
Alpha Radiation ◽  
Used Nuclear Fuel ◽  
High Let Radiation ◽  
High Let

Treatment of used nuclear fuel through solvent extraction separation processes is hindered by radiolytic damage from radioactive isotopes present in used fuel. The nature of the damage caused by the radiation may depend on the radiation type, whether it be low linear energy transfer (LET) such as gamma radiation or high LET such as alpha radiation. Used nuclear fuel contains beta/gamma emitting isotopes but also a significant amount of transuranics which are generally alpha emitters. Studying the respective effects on matter of both of these types of radiation will allow for accurate prediction and modeling of process performance losses with respect to dose. Current studies show that alpha radiation has milder effects than that of gamma. This is important to know because it will mean that solvent extraction solutions exposed to alpha radiation may last longer than expected and need less repair and replacement. These models are important for creating robust, predictable, and economical processes that have strong potential for mainstream adoption on the commercial level. The effects of gamma radiation on solvent extraction ligands have been more extensively studied than the effects of alpha radiation. This is due to the inherent difficulty in producing a sufficient and confluent dose of alpha particles within a sample without leaving the sample contaminated with long lived radioactive isotopes. Helium ion beam and radioactive isotope sources have been studied in the literature. We have developed a method for studying the effects of high LET radiation in situ via 10B activation and the high LET particles that result from the 10B(n,α)7Li reaction which follows. Our model for dose involves solving a partial differential equation representing absorption by 10B of an isentropic field of neutrons penetrating a sample. This method has been applied to organic solutions of TBP and CMPO, two ligands common in TRU solvent extraction treatment processes. Rates of degradation of TBP and CMPO and their respective degradation products in the presence of high LET radiation are presented and discussed. These results are also compared to gamma studies performed in our lab and other gamma and alpha studies found in the literature. The possible application of this method to a variety of other solvent extraction ligands to study the effects of high LET radiation is also considered.

scholarly journals Equivalency of the quality of sublethal lesions after photons and high-linear energy transfer ion beams

2017 ◽  
Vol 58 (6) ◽  
pp. 803-808 ◽  
Author(s):  
Yoshiya Furusawa ◽  
Mizuho Nakano-Aoki ◽  
Yoshitaka Matsumoto ◽  
Ryoichi Hirayama ◽  
Alisa Kobayashi ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Linear Energy Transfer ◽  
Ion Beam ◽  
Chinese Hamster ◽  
Heavy Ion ◽  
Ion Beams ◽  
X Rays ◽  
High Let ◽  
High Linear Energy Transfer

Abstract The quality of the sublethal damage (SLD) after irradiation with high–linear energy transfer (LET) ion beams was investigated with low-LET photons. Chinese hamster V79 cells and human squamous carcinoma SAS cells were first exposed to a priming dose of different ion beams at different LETs at the Heavy Ion Medical Accelerator in the Chiba facility. The cells were kept at room temperature and then exposed to a secondary test dose of X-rays. Based on the repair kinetics study, the surviving fraction of cells quickly increased with the repair time, and reached a plateau in 2–3 h, even when cells had received priming monoenergetic high-LET beams or spread-out Bragg peak beams as well as X-ray irradiation. The shapes of the cell survival curves from the secondary test X-rays, after repair of the damage caused by the high-LET irradiation, were similar to those obtained from cells exposed to primary X-rays only. Complete SLD repairs were observed, even when the LET of the primary ion beams was very high. These results suggest that the SLD caused by high-LET irradiation was repaired well, and likewise, the damage caused by the X-rays. In cells where the ion beam had made a direct hit in the core region in an ion track, lethal damage to the domain was produced, resulting in cell death. On the other hand, in domains that had received a glancing hit in the low-LET penumbra region, the SLD produced was completely repaired.

scholarly journals Immunomodulatory Effects of Radiotherapy

2020 ◽  
Vol 21 (21) ◽  
pp. 8151
Author(s):  
Sharda Kumari ◽  
Shibani Mukherjee ◽  
Debapriya Sinha ◽  
Salim Abdisalaam ◽  
Sunil Krishnan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Carbon Particle ◽  
Dna Lesions ◽  
X Rays ◽  
Adaptive Immune ◽  
High Let Radiation ◽  
Different Types ◽  
High Let ◽  
Radiation Induced ◽  
Tumor Death

Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT.

Alpha-Particle Exposure Induces Mainly Unstable Complex Chromosome Aberrations which do not Contribute to Radiation-Associated Cytogenetic Risk

2021 ◽  
Author(s):  
C. Hartel ◽  
E. Nasonova ◽  
S. Ritter ◽  
T. Friedrich
Keyword(s):  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Mitotic Cell ◽  
Peripheral Blood Lymphocytes ◽  
Small Scale ◽  
X Rays ◽  
Carcinogenic Effect ◽  
High Let Radiation ◽  
High Let ◽  
Α Particles

The mechanism underlying the carcinogenic potential of α radiation is not fully understood, considering that cell inactivation (e.g., mitotic cell death) as a main consequence of exposure efficiently counteracts the spreading of heritable DNA damage. The aim of this study is to improve our understanding of the effectiveness of α particles in inducing different types of chromosomal aberrations, to determine the respective values of the relative biological effectiveness (RBE) and to interpret the results with respect to exposure risk. Human peripheral blood lymphocytes (PBLs) from a single donor were exposed ex vivo to doses of 0–6 Gy X rays or 0–2 Gy α particles. Cells were harvested at two different times after irradiation to account for the mitotic delay of heavily damaged cells, which is known to occur after exposure to high-LET radiation (including α particles). Analysis of the kinetics of cells reaching first or second (and higher) mitosis after irradiation and aberration data obtained by the multiplex fluorescence in situ hybridization (mFISH) technique are used to determine of the cytogenetic risk, i.e., the probability for transmissible aberrations in surviving lymphocytes. The analysis shows that the cytogenetic risk after α exposure is lower than after X rays. This indicates that the actually observed higher carcinogenic effect of α radiation is likely to stem from small scale mutations that are induced effectively by high-LET radiation but cannot be resolved by mFISH analysis.

scholarly journals The effect of low LET (Linear Energy Transfer) ionizing radiation to catalase activity of wistar’s submandibular gland

2016 ◽  
Vol 1 (3) ◽  
pp. 145
Author(s):  
Nevy T. Putri ◽  
Sarianoferni Sarianoferni ◽  
Endah Wahjuningsih
Keyword(s):  
Energy Transfer ◽  
Ionizing Radiation ◽  
Submandibular Gland ◽  
Rattus Norvegicus ◽  
Catalase Activity ◽  
Linear Energy Transfer ◽  
Submandibular Salivary Gland ◽  
X Rays ◽  
X Ray ◽  
Bonferroni Test

Intraoral periapical radiograph examination is the additional examination which is the most widely used in Dentistry. This radiograph examination using an x-ray ionizing radiation with low LET (Linear Energy Transfer), and may affect submandibular salivary gland. Ionizing radiation exposure can cause damage by inducing a series of changes at the molecular and cellular level. This study aimed to prove the effects of x-ray ionizing radiation with low LET towards the catalase activity of Rattus norvegicus strain Wistar’s submandibular gland. The subjects were 28 male Wistar rats and divided into 4 groups (n=7). Three groups were exposed 4, 8 and 14 times to radiation with 0.002 µSv for each exposure. The catalase activity of each rat was examined by a spectrophotometer. Data were analyzed using one-way ANOVA followed by Bonferroni test. The results showed the average of catalase activity on Wistar rat’s submandibular gland, respectively for: 0.150±0.0895 (KK), 0.1405±0.0607 (K1), 0.1228±0.0290 (K2), 0.1227±0.0556 (K3). Data showed significant differences of catalase activity between test groups, but showed not significant differences of catalase activity between each groups of Rattus norvegicus strain Wistar’s submandibular gland. In this study concluded decreased catalase activity of Rattus norvegicus strain Wistar’s submandibular gland resulting from x-rays ionizing radiation by 4 times, 8 times and 14 times exposures.

Linear energy transfer dependence of transient yields in water irradiated by 150 keV – 500 MeV protons in the limit of low dose rates

2020 ◽  
Vol 98 (8) ◽  
pp. 427-433
Author(s):  
Ahmed Alanazi ◽  
Jintana Meesungnoen ◽  
Jean-Paul Jay-Gerin
Keyword(s):  
Energy Transfer ◽  
Linear Energy Transfer ◽  
Low Dose ◽  
High Dose ◽  
Dose Rates ◽  
Normal Tissues ◽  
High Let ◽  
Proton Track ◽  
Electron And Photon ◽  
Anti Tumor Activity

FLASH radiotherapy is a new irradiation method in which large doses of ionizing radiation are delivered to tumors almost instantly (a few milliseconds), paradoxically sparing healthy tissue while preserving anti-tumor activity. Although this technique is primarily studied in the context of electron and photon therapies, proton delivery at high dose rates can also reduce the adverse side effects on normal cells. So far, no definitive mechanism has been proposed to explain the differences in the responses to radiation between tumor and normal tissues. Given that living cells and tissues consist mainly of water, we set out to study the effects of high dose rates on the radiolysis of water by protons in the energy range of 150 keV – 500 MeV (i.e., for linear energy transfer (LET) values between ∼72.2 and 0.23 keV/μm, respectively) using Monte Carlo simulations. To validate our methodology, however, we, first, report here the results of our calculations of the yields (G values) of the radiolytically produced species, namely the hydrated electron ([Formula: see text]), •OH, H•, H2, and H2O2, for low dose rates. Overall, our simulations agree very well with the experiment. In the presence of oxygen, [Formula: see text] and H• atoms are rapidly converted into superoxide anion or hydroperoxyl radicals, with a well-defined maximum of [Formula: see text] at ∼1 μs. This maximum decreases substantially when going from low-LET 500 MeV to high-LET 150 keV irradiating protons. Differences in the geometry of the proton track structure with increasing LET readily explain this diminution in [Formula: see text] radicals.

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