Direct effects of ionizing radiation on macromolecules

In the dry or frozen states, macromolecules are damaged directly by interactions with ionizing radiation. As γ‐rays and high‐energy electrons randomly ionize orbital electrons in their path, larger molecules are more likely to suffer an interaction with these radiations. In each interaction, energy is transferred to the struck molecule, resulting in irreversibly broken covalent bonds. There is an extensive literature describing these radiation modifications in both synthetic and biopolymers. Although many different properties are measured, there emerges a similar picture of the nature of radiation damage that is common to all macromolecules. The techniques used in study of one species may be used to resolve questions raised in the other class of macromolecules. © 2011 Wiley Periodicals, Inc.? J Polym Sci Part B: Polym Phys, 2011     

Vacuum-UV and Low-Energy Electron-Induced DNA Strand Breaks – Influence of the DNA Sequence and Substrate

DNA is effectively damaged by radiation, which can on the one hand lead to cancer and is on the other hand directly exploited in the treatment of tumor tissue. DNA strand breaks are already induced by photons having an energy below the ionization energy of DNA. At high photon energies, most of the DNA strand breaks are induced by low-energy secondary electrons. In the present study we quantified photon and electron induced DNA strand breaks in four different 12mer oligonucleotides. They are irradiated directly with 8.44 eV vacuum ultraviolet (VUV) photons and 8.8 eV low energy electrons (LEE). By using Si instead of VUV transparent CaF₂ as a substrate the VUV exposure leads to an additional release of LEEs, which have a maximum energy of 3.6 eV and can significantly enhance strand break cross sections. Atomic force microscopy is used to visualize strand breaks on DNA origami platforms and to determine absolute values for the strand break cross sections. Upon irradiation with 8.44 eV photons all the investigated sequences show very similar strand break cross sections in the range of 1.7–2.3×10⁻¹⁶ cm². The strand break cross sections for LEE irradiation at 8.8 eV are one to two orders of magnitude larger than the ones for VUV photons, and a slight sequence dependence is observed. The sequence dependence is even more pronounced for LEEs with energies <3.6 eV. The present results help to assess DNA damage by photons and electrons close to the ionization threshold.     

Molecular dynamics simulation of clustered DNA damage sites containing 8-oxoguanine and abasic site

Clustered DNA damage sites induced by ionizing radiation have been suggested to have serious consequences to organisms, such as cancer, due to their reduced probability to be repaired by the enzymatic repair machinery of the cell. Although experimental results have revealed that clustered DNA damage sites effectively retard the efficient function of repair enzymes, it remains unclear as to what particular factors influence this retardation. In this study, approaches based on molecular dynamics (MD) simulation have been applied to examine conformational changes and energetic properties of DNA molecules containing clustered damage sites consisting of two lesioned sites, namely 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic (AP) site, located within a few base pairs of each other. After 1 ns of MD simulation, one of the six DNA molecules containing a clustered damage site develops specific characteristic features: sharp bending at the lesioned site and weakening or complete loss of electrostatic interaction energy between 8-oxoG and bases located on the complementary strand. From these results it is suggested that these changes would make it difficult for the repair enzyme to bind to the lesions within the clustered damage site and thereby result in a reduction of its repair capacity.     

Analysis of Diazofluorene DNA Binding and Damaging Activity: DNA Cleavage by a Synthetic Monomeric Diazofluorene

The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D‐ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be a significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies.     

DNA binding hydroxyl radical probes

The hydroxyl radical is the primary mediator of DNA damage by the indirect effect of ionizing radiation. It is a powerful oxidizing agent produced by the radiolysis of water and is responsible for a significant fraction of the DNA damage associated with ionizing radiation. There is therefore an interest in the development of sensitive assays for its detection. The hydroxylation of aromatic groups to produce fluorescent products has been used for this purpose. We have examined four different chromophores, which produce fluorescent products when hydroxylated. Of these, the coumarin system suffers from the fewest disadvantages. We have therefore examined its behavior when linked to a cationic peptide ligand designed to bind strongly to DNA.     

Re-Emerging Field of Lignocellulosic Fiber – Polymer Composites and Ionizing Radiation Technology in their Formulation

Natural cellulose-based fibers offer low cost, low density composite reinforcement with good strength and stiffness. Because of their annual renewability and biodegradability, natural fibers have materialized as environmentally-friendly alternatives to synthetic fibers in the last two decades. They are replacing synthetic materials in some traditional composites in industrial manufacturing sectors such as automotive, construction, furniture, and other consumer goods. In this work, the use of lignocellulosic fibers in green materials engineering, particularly their application as polymeric composite reinforcement and surface treatment via ionizing radiation are reviewed. Because these cellulose-based materials are intrinsically hydrophilic, they require surface modification to improve their affinity for hydrophobic polymeric matrices, which enhances the strength, durability, and service lifetime of the resulting lignocellulosic fiber-polymer composites. In spite of a long history of using chemical methods in the modification of material surfaces, including the surface of lignocellulosic fibers, recent research leans instead towards application of ionizing radiation. Ionizing radiation methods are considered superior to chemical methods, as they are viewed as clean, energy saving, and environmentally friendly. Recent applications of controlled ionizing radiation doses in the formulation of natural fiber –reinforced polymeric composites resulted in products with enhanced fiber-polymer interfacial bonding without affecting the inner structure of lignocellulosic fibers. These applications are critically reviewed in this contribution.     

Insight into the Mechanism of the Initial Reaction of an OH Radical with DNA/RNA Nucleobases: A Computational Investigation of Radiation Damage

Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X‐D/6‐311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10^?12, 5.64×10^?11, 2.01×10^?11, and 5.03×10^?12 cm³ molecules^?1 s^?1, respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C₈ as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C₅ and C₆ competes with the abstraction of H₁. Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases.     

Sensitizing DNA Towards Low‐Energy Electrons with 2‐Fluoroadenine

2‐Fluoroadenine (^2FA) is a therapeutic agent, which is suggested for application in cancer radiotherapy. The molecular mechanism of DNA radiation damage can be ascribed to a significant extent to the action of low‐energy (<20 eV) electrons (LEEs), which damage DNA by dissociative electron attachment. LEE induced reactions in ^2FA are characterized both isolated in the gas phase and in the condensed phase when it is incorporated into DNA. Information about negative ion resonances and anion‐mediated fragmentation reactions is combined with an absolute quantification of DNA strand breaks in ^2FA‐containing oligonucleotides upon irradiation with LEEs. The incorporation of ^2FA into DNA results in an enhanced strand breakage. The strand‐break cross sections are clearly energy dependent, whereas the strand‐break enhancements by ^2FA at 5.5, 10, and 15 eV are very similar. Thus, ^2FA can be considered an effective radiosensitizer operative at a wide range of electron energies.     

Phenylpropanoids in radioregulation: double edged sword

Radiotherapy, frequently used for treatment of solid tumors, carries two main obstacles including acquired radioresistance in cancer cells during radiotherapy and normal tissue injury. Phenylpropanoids, which are naturally occurring phytochemicals found in plants, have been identified as potential radiotherapeutic agents due to their anti-cancer activity and relatively safe levels of cytotoxicity. Various studies have proposed that these compounds could not only sensitize cancer cells to radiation resulting in inhibition of growth and cell death but also protect normal cells against radiation-induced damage. This review is intended to provide an overview of recent investigations on the usage of phenylpropanoids in combination with radiotherapy in cancer treatment.     

Chemistry and biology of DNA repair

Numerous agents of endogenous and exogenous origin damage DNA in our genome. There are several DNA-repair pathways that recognize lesions in DNA and remove them through a number of diverse reaction sequences. Defects in DNA-repair proteins are associated with several human hereditary syndromes, which show a marked predisposition to cancer. Although DNA repair is essential for a healthy cell, DNA-repair enzymes counteract the efficiency of a number of important antitumor agents that exert their cytotoxic effects by damaging DNA. DNA-repair enzymes are therefore also targets for drug design. DNA-repair processes differ greatly in their nature and complexity. Whereas some pathways only require a single enzyme to restore the original DNA sequence, others operate through the coordinated action of 30 or more proteins. Our understanding of the genetic, biochemical, and structural basis of DNA repair and related processes has increased dramatically over the past decade. This review summarizes the latest developments in this field.     

miR-9 and let-7g enhance the sensitivity to ionizing radiation by suppression of NFκB1

The activation of nuclear factor-kappa B1 (NFkB1) in cancer cells may confer resistance to ionizing radiation (IR). To enhance the therapeutic efficiency of IR in lung cancer, we screened for microRNAs (miRNAs) that suppress NFkB1 and observed their effects on radiosensitivity in a human lung cancer cell line. From time series data of miRNA expression in γ-irradiated H1299 human lung cancer cells, we found that the expression of miR-9 was inversely correlated with that of NFκB1. Overexpression of miR-9 down-regulated the level of NFκB1 in H1299 cells, and the surviving fraction of γ-irradiated cells was decreased. Interestingly, let-7g also suppressed the expression of NFκB1, although there was no canonical target site for let-7g in the NFκB1 3' untranslated region. From these results, we conclude that the expression of miR-9 and let-7g could enhance the efficiency of radiotherapy for lung cancer treatment through the inhibition of NFκB1.     

小剂量电离辐射对生物体的作用

本文调研了国内外有关小剂量电离辐射对生物体作用的实验研究。许多实验结果指出,辐射引起生物体近期辐射损伤的阈值一般不低于01Gy,并且小剂量电离辐射对机体免疫功能有促进作用,小剂量预辐照后能对大剂量辐照产生适应性。因此,有学者提出小剂量有益的观点,很具有启发性。然而由于对小剂量辐射生物效应的资料掌握不够,对小剂量照射还需要继续进行深入的研究。     

On the Development of the VIPAR Polymer Gel Dosimeter for Three-Dimensional Dose Measurements

Summary: The new polymer gel dosimeter, based on the modification of the VIPAR gel composition, is described for the purpose of radiation dose distribution measurement in radiotherapy. It features increased concentration of the two VIPAR substrates: N-vinylpyrrolidone (8%) and gelatine (7.5%) (N,N′-methylenebisacrylamide was maintained at 4%), and the addition of copper sulphate (0.0008%) and ascorbic acid (0.007%) in order to facilitate the preparation through elimination of the need for deoxygenation of the gel. Following the exposure to ionizing radiation, polymerisation and cross-linking of the new gel monomers occurs retaining the spatial distribution of absorbed dose and causing opacity of the gel. Quantitative parameters of the new gel dose response were studied using magnetic resonance imaging to relate polymerisation induced physicochemical changes of the gel to dose. The dose threshold is found significantly lower than that of the original VIPAR gel. The linear part of measured spin-spin relaxation rate R₂(D) ( = 1/T₂(D)) reaches up to 35 Gy. Its slope and an intercept are slightly higher relative to the original VIPAR. The efficiency of the new polymer gel-magnetic resonance imaging dosimeter was also tested for dose verification of a 3D dose distribution planned by a commercially available treatment planning software (Eclipse External Beam v.6.5) and delivered by a 6 MV medical linear accelerator. The new polymer gel is proposed to be called, VIPAR^nd (after VIPAR-normoxic-double).