Advances in radiation biology: Radiosensitization in DNA and living cells

doi:10.1016/j.susc.2008.10.049

Surface Science

Volume 603, Issues 10–12, 1 June 2009, Pages 1953-1960

https://doi.org/10.1016/j.susc.2008.10.049 Get rights and content

Abstract

One fundamental goal of radiation biology is the evolution of concepts and methods for the elaboration of new approaches and protocols for the treatment of cancers. In this context, the use of fast ions as ionizing particles offers the advantage of optimizing cell killing inside the tumor whilst preserving the surrounding healthy tissues. One extremely promising strategy investigated recently is the addition of radiosensitizers in the targeted tissue. The optimization of radiotherapy with fast ions implies a multidisciplinary approach to ionizing radiation effects on complex living systems, ranging from studies on single molecules to investigations of entire organisms.

In this article we review recent studies on ion induced damages in simple and complex biological systems, from DNA to living cells. The specific aspect of radiosensitization induced by metallic atoms is described. As a fundamental result, the addition of sensitizing compounds with ion irradiation may improve therapeutic index in cancer therapy. In conclusion, new perspectives are proposed based on the experience and contribution of different communities including Surface Sciences, to improve the development of radiation biology.

Introduction

Radiation biology concerns the understanding and control of the consequences of radiation exposure of living organisms. Different radiation sources and advanced techniques are used to explore various aspects of modern radiation biology and clinical applications in radiotherapy. It is widely accepted that the early spatial distribution of energy deposition following ionizing radiation action on biomolecular architectures is decisive for the prediction and control of damage in cells and tissues. A fundamental understanding of the basic mechanisms (see Scheme 1) underlying radiation damage in DNA and in living cells, ranging from the early stage processes over DNA lesions, cell signaling, genomic instability, and apoptosis should have in the near future many practical consequences.

Up to now, X-rays and accelerated electron beams are the standard ionizing radiations currently used for cancer radiotherapy applied to millions of patients around the world. It is generally easy to kill cells by application of ionizing radiation. The fundamental problem in radiation based cancer therapies is the optimization of the cell killing inside the tumor whilst at the same time preserving the surrounding healthy tissues. In this context, new protocols have been developed with the purpose of focusing and maximizing the energy deposition of the ionizing particles into the volume of the tumor. Here, one extremely promising strategy is the use of fast ions as ionizing particles. The implementation of radiation therapy using ions as ionizing particles is a quickly developing field of investigation. Even though they are still emerging techniques, proton and hadron therapies represent promising methods for the specific treatment of deeply seated tumors and radioresistant cancers [1], [2], [3]. The unique potential of this approach lies in the specific physical properties of fast atomic ions when penetrating matter. In particular, the variation of the Linear Energy Transfer (LET) of the incident particles with the penetration depth exhibits a strong enhancement at the end of the particle tracks (i.e. the Bragg peak). This characteristic property offers the advantage of delivering the dose into a relatively well-defined volume, making it possible to preserve the healthy tissue located around the solid tumor (Fig. 1).

Another possible strategy to enhance cell killing is the use of radiosensitizers, i.e. the administration of chemical or pharmacological agents to the tumor. Recently, the application of heavy metal loaded salts to DNA or living cells has been proposed for irradiation by either X-ray or γ-ray [4], [5]. Encouraging results have for instance been obtained in the treatment of gliomas at a preclinical level using a combination of chemotherapy with cis-platinum, and radiotherapy using monochromatic X-rays [6].

This article outlines a possible strategy to fulfill the understanding of radiation damage and in particular of radiosensitization mechanisms when fast ions are used as ionizing radiation. This research consists of a multidisciplinary activity with the contribution of groups exhibiting different scientific background, from physic (including Surface Science) to biology. These aspects are successively addressed in the paper.

In the first part, a study concerning the effects induced by the direct interaction of ions with DNA lyophilized at surfaces and irradiated in vacuum, is reported.

The second and third parts, introduce the basis concerning the effects of radiation and radiosensitization in biological conditions, on DNA and living cells, respectively. First, experiments of irradiation performed on DNA in solution, underline the role of water radicals in the degradation of biological molecules. Our work focuses on the radiosensitization induced by heavy metal compounds (platinum salts). In a second step, these effects are extrapolated to living cells. These preliminary results demonstrate clearly that the association of irradiation by fast ions with the addition of high-Z atom radiosensitizers is a very promising method for improving the treatments of cancer.

It is the aim of this article to show that a better understanding of the fundamental processes of ion induced radiation damage at a molecular level is a necessary step for the optimization of radiotherapy with fast ions. This new approach of the radiation biology emerges with the collaborative work of different communities. It therefore opens new perspectives in different disciplines. In the last section, some challenges are submitted to the Surface Science community in particular. As an end point, this research aims at the development of new concepts, protocols and methods for medical purposes.

Section snippets

Ion induced damage in lyophilized DNA

When living systems are exposed to ionizing radiation, damage in nuclear DNA is generally considered as the most dramatic effect for the cells [7], [8], [9], [10]. Induction of double strand breaks in the helix (DSB) is believed to be at the origin of the cell death induction. This DNA damage is expected to be dependent on the incident ionizing particles. In particular, it is known that atomic ion beams are more efficient than either X-rays or γ-rays to induce double strand breaks in cellular

Ion induced damage in hydrated DNA: radiosensitization

Fast ions are used as efficient ionizing particles in cancer treatments. The molecular effects of ions interacting with the biological matter are characterized in DNA solvated in Tris-EDTA (ethylenediaminetetraacetic acid) solution (see Scheme 4, Scheme 5). In these biological-like conditions, solvent mediated processes (indirect process), related to the production of water radicals are present (see Scheme 1) [23], [24]. A large number of studies can be found in the literature where

Ion induced damage in living cells: radiosensitization

These experiments aim at the assessment whether an enhancement of the death rate occurs upon exposure to fast atomic ions, when cells are loaded with platinum containing molecules. Experiments on living cells incubated with platinum salts have been performed. Thanks to the very low toxicity of the terpiridyne platinum chloride (PtTC), the specific role of platinum atoms in the induction of cells death could be investigated. The cell Surviving Fractions (SF) are reported in Fig. 7 for cells

Conclusions and perspectives

Radiation biology is a challenging and broad field of interdisciplinary research that benefits from the most recent progresses in physics, physical-chemistry, molecular biology, as well as genomic and proteomic. One challenge of radiation biology is the complete understanding of the fundamental spatio-temporal events triggered by an initial energy deposition inside confined clusters of ionization and evolving over several orders of magnitude, typically from femtosecond and sub-micrometric

References (43)

G. Kraft
Prog. Part. Nucl. Phys.
(2000)
C. Giustranti et al.
Biochimie
(2000)
S. Lacombe et al.
Surf. Sci.
(1998)
B. Kasemo
Surf. Sci.
(2002)
D.G. Castner et al.
Surf. Sci.
(2002)
L.M. Miller et al.
Biochem. Biophys. Acta (BBA) – Biomembranes
(2006)
B. Brozek-Pluska et al.
Radiat. Phys. Chem.
(2005)
W.R. Holley et al.
Radiat. Res.
(1990)
H. Tsujii et al.
Current Status of Carbon Ion Radiotherapy
J. Rad. Res.
(2007)
L.X. Yang et al.
Radiat. Res.
(1995)

S. Corde et al.

J. Balosso. Radiat. Res.

(2002)

M.C. Biston et al.

J. Balosso. Cancer Res.

(2004)

R.B. Painter

I.G. Iliakis

Bioassays

(1991)

D.T. Goodhead et al.

Int. J. Radiat. Biol.

(1993)

M. Pinto et al.

Radiat. Res.

(2005)

R. Hirayama et al.

J. Radiat. Res.

(2005)

K.M. Prise et al.

Radiat. Res.

(2001)

T. Schlatholter et al.

Phys. Scripta

(2006)

L. Sellami et al.

Rev. Scient. Instr.

(2007)

Z.W. Deng et al.

Phys. Rev A

(2006)

Cited by (19)

Monte carlo and molecular dynamics simulations of surface modification of DNA interacted with ultra-low-energy carbon atoms
2016, Surface and Coatings Technology
Citation Excerpt :
In previous study on yeast cells, significant morphological damage and DNA strand breaks after low-energy nitrogen ion bombardment below 40 keV were observed by scanning electron microscopy (SEM) and immunofluorescence assays [3,4]. Irradiation of cells leads to the structural change of bases in the DNA, causing mispairing and mutation which can result in new varieties of plants and animals and also induce cancers of human tissues and death of cells [5,6]. Along with experimental efforts, in which low energy keV ions bombarded naked DNA in vacuum and DNA strand breaks and mutation induction were discovered [7–13], atomistic molecular simulation can reveal the nature of interaction at molecular interaction.
DNA surface and DNA strand breaks of 12 base pairs of alternating poly-AT double strands of DNA in A form were investigated by Monte Carlo simulations to find the preferential binding sites and Langevin Molecular Dynamics simulations after exposure to 0.2, 20, and 200 eV carbon atoms. Final simulated structures were further optimized using the AMBER force field and details in the surface changes, the interaction between DNA and carbon and the interaction between single-stranded strand and its pair were investigated. The solvent accessible area surface and volume of DNA were determined and significant differences observed under higher energy and temperature conditions. Both simulations concluded that under the low energy irradiation and low temperature, carbon atoms could explore the surface and interact to the preferential sites at phosphate oxygen or nitrogen in base pairing, dominated by the local base pair shift in a stagger and buckle manner, while under higher energy irradiation more severe base pair shift could be caused in combination with propeller and opening manner and several bonds could be elongated to lead to DNA damage.
Protective effect of dendrodoine analog, an aminothiazole derivative against X-radiation induced hepatocellular damage in mice
2012, Environmental Toxicology and Pharmacology
Citation Excerpt :
However, as previously reported, it could be suggested that lower concentrations of DA might not be enough to quench all the radicals generated by radiation and higher concentrations of DA might have reacted with some other ligands in the system and thus might not be completely available for quenching the free radicals (Kalpana et al., 2010). X-rays and accelerated electron beams are the standard ionizing radiations used for cancer radiotherapy applied to millions of patients around the world (Lacombe and Le Sech, 2009). Exposure to ionizing radiation causes radiolysis of water in tissues leading to generation of ROS which are known to affect the antioxidant defense systems and induce LPO (Riley, 1994).
This study evaluated the radioprotective effect of dendrodoine analog (DA) against radiation-induced damage in the liver of mice. The study was divided into two phases; in the first phase, the effective concentration of DA was fixed by performing a survival study. In the second phase, the fixed effective concentration of DA was orally administered to mice to evaluate its radioprotective efficacy by performing various assays. The results indicated that the radiation-induced decrease in the activities of antioxidant enzymes, increase in thiobarbituric acid reactive substances (TBARS) and comet parameters were altered by pre-administration with the effective concentration of DA which restored the antioxidant status to near normal and decreased the level of the TBARS and comet parameters. The histopathological examinations further confirmed the hepatoprotective effect of DA in mice. Thus, the current study showed DA to be an effective radioprotector against radiation induced damage in the liver of mice.
Ultrafast charge delocalization dynamics in aqueous electrolytes: New insights from Auger electron spectroscopy
2012, Chemical Physics Letters
Citation Excerpt :
The new shallower core–holes can then decay by electron emission and, after several steps, result in highly charged ions and potent radicals which may cause severe damage to biomolecules in the vicinity of the initial absorber – all this being initiated by the relaxation of a single core–hole. Understanding the mechanistic details of such relaxation processes in aqueous environments, i.e. what factors govern the availability of different decay channels and their respective rates, are of both fundamental interest (e.g. for testing models of ultrafast molecular dynamics under far-from-equilibrium conditions) and applications (e.g. for understanding and controlling radiation damage of biological material in radiotherapeutic treatments for more targeted effects) [2–5]. Experimental studies of charge delocalization dynamics following core–hole decays in the aqueous phase are challenging for several reasons, especially if they are performed explicitly in the time-domain, i.e. in a pump–probe scheme.
We review the basic principles of ultrafast charge delocalization phenomena in aqueous electrolytes following core-level photoionization and resonant core-level excitations, and describe how these processes can be probed using Auger electron spectroscopy. The use of the core–hole clock method to extract dynamical information from Auger spectra is described. By a number of examples we demonstrate how the efficiency for ultrafast charge transfer phenomena on the low femtosecond timescale is determined not only by factors such as charge, polarizability and solvated radius of the ionic solutes but also by the dominant interactions of the ionized site with its surroundings in the intermediate state.
Combined quantum-mechanics/molecular-mechanics dynamics simulation of A-DNA double strands irradiated by ultra-low-energy carbon ions
2011, Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms
Citation Excerpt :
Coincident with recent rapid research developments in heavy ion therapy, ion beam biotechnology and life hazard studies for space missions, low-energy ion irradiation of DNA is a hot topic (e.g. [1,2]).
In order to promote understanding of the fundamentals of ultra-low-energy ion interaction with DNA, molecular dynamics simulations using combined quantum-mechanics/molecular-mechanics of poly-AT and poly-GC A-DNA double strands irradiated by <200 eV carbon ions were performed to investigate the molecular implications of mutation bias. The simulations were focused on the responses of the DNA backbones and nitrogenous bases to irradiation. Analyses of the root mean square displacements of the backbones and non-hydrogen atoms of base rings of the simulated DNA structure after irradiation revealed a potential preference of DNA double strand separation, dependent on the irradiating energy. The results show that for the backbones, the large difference in the displacement between poly-GC and poly-AT in the initial time period could be the reason for the backbone breakage; for the nitrogenous base pairs, A–T is 30% more sensitive or vulnerable to ion irradiation than G–C, demonstrating a preferential, instead of random, effect of irradiation-induced mutation.
Protection against X-ray radiation-induced cellular damage of human peripheral blood lymphocytes by an aminothiazole derivative of dendrodoine
2010, Chemico-Biological Interactions
Citation Excerpt :
It is widely accepted that the early spatial distribution of energy deposition following ionizing radiation action on biomolecular architectures is decisive for the prediction and control of damage in cells and tissues. Currently, X-rays and accelerated electron beams are the standard ionizing radiations currently used for cancer radiotherapy applied to millions of patients around the world [29]. The alkaline single-cell microgel electrophoresis assay (or comet assay) has been shown to be useful for the assessment of DNA damage and repair within epidemiologic studies, because it is a fast and reliable assay that needs only a small number of cells [30].
The present study was aimed to evaluate the radioprotective efficacy of dendrodoine analog (DA), an aminothiazole derivative against X-ray radiation-induced cellular damage in cultured human peripheral blood lymphocytes. Different concentrations of DA (2, 4, 6, 8, 10 μg/ml or 6.15, 12.29, 18.44, 24.59, 30.73 μM) were pre-incubated with lymphocytes for 30 min prior to irradiation [4 Gy] and the micronuclei (MN) scoring and comet assay were performed to fix the effective concentration of DA against 4 Gy irradiation-induced cellular damage. The results indicated that among all the concentrations, 6 μg/ml concentration of DA showed optimum protection by effectively decreasing the MN frequencies and comet attributes. Based on the above results, 6 μg/ml concentration of DA was fixed as the effective dose to further investigate its radioprotective efficacy. This was carried out by pre-incubating the lymphocytes with 6 μg/ml concentration of DA followed by exposure of the lymphocytes to different doses (1, 2, 3 and 4 Gy) of radiation and investigating the radiation-induced genetic damage (MN, comet assay, DNA fragmentation assay) and biochemical changes (changes in the level of enzymic and non-enzymic antioxidants, lipid peroxidation). The results indicated a dose-dependent increase in both genetic damage and thiobarbituric acid reactive substances (TBARS), accompanied by a significant decrease in the antioxidant status in the irradiated groups compared to DA treated groups which modulated the toxic effects through its antioxidant potential. Thus the current study shows DA to be an effective radioprotector against X-ray radiation induced in vitro cellular damage in lymphocytes.
Enhancement of radiation effect by heavy elements
2010, Mutation Research - Reviews in Mutation Research
The enhancement of radiobiological effects by heavy elements is reviewed. As an underlying mechanism, Auger effects have been stressed which can be induced via inner-shell photoabsorption or via excitation and/or ionization by secondary electrons. Latter channel of Auger induction expands the applicability of Auger enhancing phenomena to electron and hadron therapy. After discussion on the required characteristics for radiosensitizers, possibility of nanoparticles of Au or Pt is mentioned since they could be synthesized or modified as ideal radiosensitizers.

View all citing articles on Scopus

View full text

Advances in radiation biology: Radiosensitization in DNA and living cells

Abstract

Introduction

Section snippets

Ion induced damage in lyophilized DNA

Ion induced damage in hydrated DNA: radiosensitization

Ion induced damage in living cells: radiosensitization

Conclusions and perspectives

Prog. Part. Nucl. Phys.

Biochimie

Surf. Sci.

Surf. Sci.

Surf. Sci.

Biochem. Biophys. Acta (BBA) – Biomembranes

Radiat. Phys. Chem.

Radiat. Res.

Current Status of Carbon Ion Radiotherapy

J. Rad. Res.

Radiat. Res.

J. Balosso. Radiat. Res.

J. Balosso. Cancer Res.

Bioassays

Int. J. Radiat. Biol.

Radiat. Res.

J. Radiat. Res.

Radiat. Res.

Phys. Scripta

Rev. Scient. Instr.

Phys. Rev A