scholarly journals From DNA Radiation Damage to Cell Death: Theoretical Approaches

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Francesca Ballarini
Keyword(s):  
Cell Death ◽  
Chromosome Aberrations ◽  
Mechanistic Model ◽  
Local Effect ◽  
Alpha Particles ◽  
Quadratic Model ◽  
Carbon Ions ◽  
Dna Double Strand Breaks ◽  
Linear Quadratic ◽  
Theoretical Approaches

Some representative models of radiation-induced cell death, which is a crucial endpoint in radiobiology, were reviewed. The basic assumptions were identified, their consequences on predicted cell survival were analyzed, and the advantages and drawbacks of each approach were outlined. In addition to “historical” approaches such as the Target Theory, the Linear-Quadratic model, the Theory of Dual Radiation Action and Katz' model, the more recent Local Effect Model was discussed, focusing on its application in Carbon-ion hadrontherapy. Furthermore, a mechanistic model developed at the University of Pavia and based on the relationship between cell inactivation and chromosome aberrations was presented, together with recent results; the good agreement between model predictions and literature experimental data on different radiation types (photons, protons, alpha particles, and Carbon ions) supported the idea that asymmetric chromosome aberrations like dicentrics and rings play a fundamental role for cell death. Basing on these results, a reinterpretation of the TDRA was also proposed, identifying the TDRA “sublesions” and “lesions” as clustered DNA double-strand breaks and (lethal) chromosome aberrations, respectively.

scholarly journals The evolution of tumour composition during fractionated radiotherapy: implications for outcome

2017 ◽  
Author(s):  
Thomas D. Lewin ◽  
Philip K Maini ◽  
Eduardo G Moros ◽  
Heiko Enderling ◽  
Helen M Byrne
Keyword(s):  
Cell Death ◽  
Oxygen Concentration ◽  
Tumour Response ◽  
Reaction Diffusion Equation ◽  
Radiation Response ◽  
Quadratic Model ◽  
Linear Quadratic ◽  
Fractionated Radiotherapy ◽  
Radiation Induced ◽  
Local Oxygen

AbstractCurrent protocols for delivering radiotherapy are based primarily on tumour stage and nodal and metastases status, even though it is well known that tumours and their microenvironments are highly heterogeneous. It is well established that the local oxygen tension plays an important role in radiation-induced cell death, with hypoxic tumour regions responding poorly to irradiation. Therefore, to improve radiation response, it is important to understand more fully the spatiotemporal distribution of oxygen within a growing tumour before and during fractionated radiation. To this end, we have extended a spatially-resolved mathematical model of tumour growth first proposed by Greenspan (Stud. Appl. Math., 1972) to investigate the effects of oxygen heterogeneity on radiation-induced cell death. In more detail, cell death due to radiation at each location in the tumour, as determined by the well-known linear-quadratic model, is assumed also to depend on the local oxygen concentration. The oxygen concentration is governed by a reaction-diffusion equation that is coupled to an integro-differential equation that determines the size of the assumed spherically-symmetric tumour. We combine numerical and analytical techniques to investigate radiation response of tumours with different intra-tumoral oxygen distribution profiles. Model simulations reveal a rapid transient increase in hypoxia upon re-growth of the tumour spheroid post-irradiation. We investigate the response to different radiation fractionation schedules and identify a tumour-specific relationship between inter-fraction time and dose per fraction to achieve cure. The rich dynamics exhibited by the model suggest that spatial heterogeneity may be important for predicting tumour response to radiotherapy for clinical applications.

scholarly journals Effects of hypersensitivity and induced radioresistance in CHO-K1 cells following exposure to gamma-rays and accelerated carbon ions

2021 ◽  
Vol 30 (4) ◽  
pp. 156-167
Author(s):  
E.V. Koryakina ◽  
◽  
V.I. Potetnya ◽  
M.V. Troshina ◽  
R.M. Baykuzina ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Gamma Rays ◽  
Chromosome Aberrations ◽  
Bragg Peak ◽  
Carbon Ions ◽  
Linear Quadratic ◽  
Plateau Region ◽  
Ovary Cells ◽  
Normal Tissues ◽  
Chromosome Aberration Test

The study presents results of investigations on chromosome aberrations (CA) yield in Chinese ham-ster ovary cells after exposure to gamma-rays and accelerated carbon ions (455 MeV/amu) at doses less than 1 Gy in the pristine Bragg curve plateau and behind the Bragg peak, where normal tissues are situated in the course of radiotherapy. Initial parts of dose curves for total CA and terminal deletions frequencies differed from linear-quadratic dependence and the region of induced radioresistance were observed at 0.1-0.6 Gy for gamma-rays. The similar curve shapes were detected for carbon ions, but plateau region was shorter (0.15-0.35 Gy). Despite the uniform shape of the dose curves for the CA yield, a definite dependence of the cytogenetic effect on the linear energy transfer (LET) is observed. The CA frequency increased with LET rising in the order: gamma-irradiation (0.2 keV/μm), carbon ions at the Bragg curve plateau (10-12 keV/μm) and at the «tail» of Bragg peak (25-27 keV/μm). Outside this range, the yield of chromosome aberrations also enhanced with increasing LET in the same order. The results obtained confirm that the hypersensitivity and induced radioresistance phenomena are characteristic for low level exposure to low-LET and middle-LET radiations when chromosome aberration test is used.

scholarly journals Comparable radiation sensitivity in p53 wild-type and p53 deficient tumor cells associated with different cell death modalities

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ping Li ◽  
Xiongxiong Liu ◽  
Ting Zhao ◽  
Feifei Li ◽  
Qiqi Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Tumor Cells ◽  
Cell Lines ◽  
Radiation Sensitivity ◽  
Mitotic Catastrophe ◽  
Premature Senescence ◽  
Carbon Ions ◽  
Dna Double Strand Breaks ◽  
Dapi Staining

AbstractStudies of radiation interaction with tumor cells often take apoptosis as the desired results. However, mitotic catastrophe and senescence are also promoted by clinically relevant doses of radiation. Furthermore, p53 is a well-known transcription factor that is closely associated with radiosensitivity and radiation-induced cell death. Therefore, we aimed to investigate the involvement of radiosensitivity, cell death modalities and p53 status in response to carbon-ion radiation (CIR) here. Isogenic human colorectal cancer cell lines HCT116 (p53+/+ and p53−/−) were irradiated with high-LET carbon ions. Cell survival was determined by the standard colony-forming assay. 53BP1 foci were visualized to identify the repair kinetics of DNA double-strand breaks (DSBs). Cellular senescence was measured by SA-β-Gal and Ki67 staining. Mitotic catastrophe was determined with DAPI staining. Comparable radiosensitivities of p53+/+ and p53−/− HCT116 colorectal cells induced by CIR were demonstrated, as well as persistent 53BP1 foci indicated DNA repair deficiency in both cell lines. Different degree of premature senescence in isogenic HCT116 colorectal cancer cells suggested that CIR-induced premature senescence was more dependent on p21 but not p53. Sustained upregulation of p21 played multifunctional roles in senescence enhancement and apoptosis inhibition in p53+/+ cells. p21 inhibition further increased radiosensitivity of p53+/+ cells. Complex cell death modalities rather than single cell death were induced in both p53+/+ and p53−/− cells after 5 Gy CIR. Mitotic catastrophe was predominant in p53−/− cells due to inefficient activation of Chk1 and Chk2 phosphorylation in combination with p53 null. Senescence was the major cell death mechanism in p53+/+ cells via p21-dependent pathway. Taken together, p21-mediated premature senescence might be used by tumor cells to escape from CIR-induced cytotoxicity, at least for a time.

scholarly journals Focused Ion Microbeam Irradiation Induces Clustering of DNA Double-Strand Breaks in Heterochromatin Visualized by Nanoscale-Resolution Electron Microscopy

2021 ◽  
Vol 22 (14) ◽  
pp. 7638
Author(s):  
Yvonne Lorat ◽  
Judith Reindl ◽  
Anna Isermann ◽  
Christian Rübe ◽  
Anna A. Friedl ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Dna Damage ◽  
Spatial Clustering ◽  
Dna Lesions ◽  
Double Strand Breaks ◽  
Stimulated Emission ◽  
Nuclear Chromatin ◽  
Carbon Ions ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

Background: Charged-particle radiotherapy is an emerging treatment modality for radioresistant tumors. The enhanced effectiveness of high-energy particles (such as heavy ions) has been related to the spatial clustering of DNA lesions due to highly localized energy deposition. Here, DNA damage patterns induced by single and multiple carbon ions were analyzed in the nuclear chromatin environment by different high-resolution microscopy approaches. Material and Methods: Using the heavy-ion microbeam SNAKE, fibroblast monolayers were irradiated with defined numbers of carbon ions (1/10/100 ions per pulse, ipp) focused to micrometer-sized stripes or spots. Radiation-induced lesions were visualized as DNA damage foci (γH2AX, 53BP1) by conventional fluorescence and stimulated emission depletion (STED) microscopy. At micro- and nanoscale level, DNA double-strand breaks (DSBs) were visualized within their chromatin context by labeling the Ku heterodimer. Single and clustered pKu70-labeled DSBs were quantified in euchromatic and heterochromatic regions at 0.1 h, 5 h and 24 h post-IR by transmission electron microscopy (TEM). Results: Increasing numbers of carbon ions per beam spot enhanced spatial clustering of DNA lesions and increased damage complexity with two or more DSBs in close proximity. This effect was detectable in euchromatin, but was much more pronounced in heterochromatin. Analyzing the dynamics of damage processing, our findings indicate that euchromatic DSBs were processed efficiently and repaired in a timely manner. In heterochromatin, by contrast, the number of clustered DSBs continuously increased further over the first hours following IR exposure, indicating the challenging task for the cell to process highly clustered DSBs appropriately. Conclusion: Increasing numbers of carbon ions applied to sub-nuclear chromatin regions enhanced the spatial clustering of DSBs and increased damage complexity, this being more pronounced in heterochromatic regions. Inefficient processing of clustered DSBs may explain the enhanced therapeutic efficacy of particle-based radiotherapy in cancer treatment.

scholarly journals Growth hormone protects against radiotherapy-induced cell death

2002 ◽  
pp. 535-541 ◽  
Author(s):  
O Madrid ◽  
S Varea ◽  
I Sanchez-Perez ◽  
L Gomez-Garcia ◽  
E De Miguel ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Death ◽  
Hormone Receptor ◽  
Growth Hormone Receptor ◽  
Molecular Mechanisms ◽  
Dna Double Strand Breaks ◽  
Cell Viability Assay ◽  
Viability Assay ◽  
Rat Growth

BACKGROUND: In vivo treatment with growth hormone reduces radiation-associated mortality. The molecular mechanisms underlying this effect are unknown. It has been described that increased sensitivity to ionising radiation can be due to defects in machinery involved in detection and/or repair of DNA double-strand breaks. OBJECTIVE: To study the mechanisms involved in growth hormone action on the increased survival in irradiated cells. MATERIALS AND METHODS: CHO-4 cells stably expressing the growth hormone receptor were used. A cell viability assay was carried out to analyse the increase in survival induced by growth hormone in irradiated cells. To investigate whether the DNA repair mechanism could be implicated in this effect we performed DNA reactivation assays using pHIV-LUC and pCMV-betagal plasmids as control. Identical studies were also conducted using the radiomimetic drug, bleomycin. RESULTS: Growth hormone protects CHO-4 cells from bleomycin- and radiation-induced cell death. In pHIV-LUC transfected cells, a time-dependent decrease in luciferase activity was observed after irradiation in the absence of growth hormone. However, cells pretreated with this hormone maintained reporter activity. When cells were transfected with irradiated pHIV-LUC plasmid, only the hormone-treated cells recovered the transcriptional activity. CONCLUSIONS: Growth hormone exerts a radioprotective effect in CHO-4 cells stably transfected with the complementary DNA for the rat growth hormone receptor. The radioprotection is triggered directly by the hormone and it is also observed with bleomycin. The increased survival in response to radiation and bleomycin treatment induced by growth hormone correlates with an enhanced ability of the cells to repair damaged DNA.

scholarly journals Simulating Radiotherapy Effect in High-Grade Glioma by Using Diffusive Modeling and Brain Atlases

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Alexandros Roniotis ◽  
Kostas Marias ◽  
Vangelis Sakkalis ◽  
Georgios C. Manikis ◽  
Michalis Zervakis
Keyword(s):  
High Grade Glioma ◽  
Quadratic Model ◽  
Normal Brain ◽  
Linear Quadratic ◽  
Linear Quadratic Model ◽  
Diffusive Model ◽  
Glioma Model ◽  
Modern Application ◽  
Diffusion Tensors ◽  
Brain Atlases

Applying diffusive models for simulating the spatiotemporal change of concentration of tumour cells is a modern application of predictive oncology. Diffusive models are used for modelling glioblastoma, the most aggressive type of glioma. This paper presents the results of applying a linear quadratic model for simulating the effects of radiotherapy on an advanced diffusive glioma model. This diffusive model takes into consideration the heterogeneous velocity of glioma in gray and white matter and the anisotropic migration of tumor cells, which is facilitated along white fibers. This work uses normal brain atlases for extracting the proportions of white and gray matter and the diffusion tensors used for anisotropy. The paper also presents the results of applying this glioma model on real clinical datasets.

Sign in / Sign up

Export Citation Format

Share Document