ISSN 00063509, Biophysics, 2015, Vol. 60, No. 4, pp. 659667. Pleiades Publishing, Inc., 2015.

Original Russian Text S.V. Gudkov, N.R. Popova, V.I. Bruskov, 2015, published in Biofizika, 2015, Vol. 60, No. 4, pp. 801811.

BIOPHYSICS OF COMPLEX SYSTEMS

Radioprotective Substances: History, Trends and Prospects

S. V. Gudkova, b, c, N. R. Popovaa, and V. I. Bruskova
a

Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences,

ul. Institutskaya 3, Pushchino, Moscow oblast, 142290 Russia
bProkhorov Institute of General Physics, Russian Academy of Sciences, ul. Vavilova 38, Moscow, 119991 Russia
c
Lobachevsky National Research University, pr. Gagarina 23, Nizhny Novgorod, 603950 Russia
email: S_makariy@rambler.ru
Received May 20, 2015

AbstractThe search for efficient radioprotective substances that alleviate various effects of ionizing radia
tion has been going on for more than 6 decades. The chronology of the major discoveries in this field and the
changes in opinions, trends, and paradigms are considered in the present review. Various classes of chemical
compounds that can be administered either before or after irradiation to protect biological objects from short
and longterm effects of ionizing radiation are considered. Dosemodifying factors, recommended time of
administration, tissue specificity, and the toxicity of different classes of radioprotective substances are con
sidered and the mechanisms that underlie the actions, as well as the practical applications, of these sub
stances, are described. A section of this review is dedicated to future prospects and the directions of research
on radioprotective substances.
Keywords: ionizing radiation, modification of radiation effects, radioprotectors, adaptogens, mitigators, ther
apeutics
DOI: 10.1134/S0006350915040120

The first chemicals that alleviate the adverse effects

of ionizing radiation on the mammalian body were
discovered more than half a century ago. This effect
was named protection from radiation sickness, while
the chemicals that exert this effect were named radio
protective substances. All radioprotective agents can
be divided into three groups: radioprotectors, adapto
gens, and adsorbents [1]. The first group consists of
sulfhydryl compounds and antioxidants that exert pro
tective effects on myeloid, enteric, and cerebral tis
sues. Adaptogens enhance the bodys resistance to
radiation by activating the antioxidant system, the
repair system, and other protective systems of the
organism. Many adaptogens are substances of plant or
animal origins. They have minimal toxicity and can
affect the regulatory systems of an organism, thus acti
vating protective responses. Adsorbents protect the
organism from internal radiation and chemicals by
binding radionuclides to accelerate their excretion [2].
All radioprotective compounds may also be divided
into three groups (radioprotectors, mitigators, and
therapeutic agents) according to the time of adminis
tration. According to this classification, radioprotec
tors are substances that have a protective effect when
administered prior to or during exposure to ionizing
radiation, mitigators are administered after exposure
Abbreviations: DMF, dosemodifying factor; RSH, sulfhydryl
radioprotectors; SOD, superoxide dismutase; ACE, angio
tensin1 converting enzyme.

to ionizing radiation, but before the onset of clinical

symptoms of radiation injury, and therapeutic agents
are administered after the onset of the first clinical
symptoms of the toxic effects of radiation on the
organism. Treatment of radiation sickness is usually
based on combined therapy, that is, administration of
several pharmaceuticals to a victim who was injured by
ionizing radiation.
A specific radioprotective compound can be multi
functional, combining antioxidant and adaptogen
properties, acting as both a mitigator and a therapeutic
agent, or a radioprotector and an adsorbent; this gives
rise to exceptions from virtually all classifications.
Therefore, all substances that are capable of apparent
reduction of the dose of ionizing radiation can be
termed radioprotective drugs or substances [3].
The currently available radioprotective substances
are clearly imperfect. A socalled ideal radioprotec
tor that serves as a reference point in the search for
new chemical preparations must meet the following
requirements: (1) high efficiency, or, in other words, a
high dosemodifying factor (DMF); (2) lack of toxic
ity; (3) a convenient administration pathway (oral
administration is preferable, while subcutaneous or
intramuscular administration is somewhat less conve
nient); (4) low manufacturing costs; (5) storage stabil
ity (long shelf life, with possibility of storage in a wide
range of temperature and humidity conditions being
an advantage); (6) long duration of protective effect

659

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GUDKOV et al.

Various classes of radioprotective compounds and their descriptions

Class of compounds

Sulfhydryl compounds

Antioxidants

Inhibitors of angiotensinIconverting enzyme

Modulators and cytokines

Mechanism of action
Antiradical
Donation of the H atom
Formation of mixed disulfides
Hypoxia ()
Redox regulation ()
Antiradical
Redox regulation ()
Hypoxia ()
Stimulation of immunity ()
Effects on the reninangiotensin system
Inhibition of collagen synthesis
? ()
Stimulation of immunity
Cytokine production
Tissue hormones
?

Prostaglandins
Metal salts and metallothionein
DNAbinding agents
Hypoxiainducing compounds
Selenium

RNA, RNA hydrolysates, and nucleosides

Fullerenes
Adsorbents

Induction of metallothionein biosynthesis

Electron transfer
Compaction of chromatin ()
Hypoxia
Signaling cascades ()
Stimulation of glutathione peroxidase activity
? ()
Antiradical
Effect on repair systems
Signaling cascades
?
Antiradical
Membrane protection
?
Binding of radionuclides
Acceleration of radionuclide excretion

T*
Sp**

Dose
modifying factor

B
()

1.32.7

B
()

1.11.3

A
(+)

<1.2

A/B
(+)
B
(+)
B
(+)
B
()
B
()

1.11.4
<1.3
<1.2
<1.3
1.21.5

B/A
(+)

<1.3

B/A
(/+)

1.11.4

B
()

<1.3

A
(+)

***

* T is the time of drug administration relatively to the time of exposure to ionizing radiation; B, the drug (radioprotector) is administered
before exposure to ionizing radiation; A, the drug (mitigator) is administered after exposure to ionizing radiation. **, Sp, tissue spec
ificity; (+), the drug is tissuespecific and exerts a protective effect on a certain range of tissues only; (), the drug protects all tissues
against the effects of ionizing radiation. ***, The dosemodifying factor is difficult to estimate; since both radiation and chemical
properties of the radionuclide contribute to mortality. , The effect is weak or characteristic of selected members of the class only.
?, Other mechanisms may underlie the action of the drug.

(the effect should occur within a few minutes after

administration and persist for a few hours); and (7) the
ability to alleviate effects of various types of ionizing
radiation. The main directions of research and devel
opment of chemical radioprotection procedures are
currently the following: (1) development of radiation
protectors that alleviate the effects of external irradia
tion that cause acute radiation injury; (2) the develop
ment of radioprotective substances that increase the
resistance of normal human tissues to radiation that is
used in a clinic (for radiation therapy); (3) develop
ment of food additives and adaptogens that enhance

the resistance of living organisms to chronic irradia

tion; and (4) the development of efficient techniques
for radionuclide elimination from the body. Radiopro
tective compounds are used for preventive treatment
of individuals involved in disaster management in the
nuclear industry, urgent repair work in areas that were
exposed to radiation or contaminated with radionu
clides, and space flights, as well as patients who are
undergoing radiation therapy [46]. Radioprotective
substances will be subsequently considered according
to molecular structure, therapeutic effects, or meta
bolic function (table).
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SULFHYDRYL COMPOUNDS
The first example of the use of sulfhydryl com
pounds was presented over 60 years ago in a Science
article by Patt et al. [7] that show that cysteine has a
strong protective effect in laboratory animals that are
exposed to ionizing radiation. This work inspired
many researchers in the field of radiobiology; there
fore, early research on radioprotectors was centered
on the synthesis of sulfhydryl compounds, especially
aminothiols and phosphorothioates. The compound
WR2721 (S2(3aminopropylamino) ethyldihydro
phosphothioate), which known as Gammafos in Rus
sia and as Amifostine in the United States was among
the first compounds of this class that were successfully
used for protection from radiation. The discovery of
this compound was a significant achievement in the
development of radioprotective substances, since the
dosemodifying factor (DMF) value for WR2721
equaled 2.7 [8]. However, this compound exerted a
protective effect only when administered to animals
immediately prior to exposure to ionizing radiation,
since the halflife of the drug in blood plasma was less
than 10 min [9]. Other phosphorothioates with a
slightly modified structure, such as S2(3methy
laminopropylamino)ethylphosphorothioate
(WR
3689) and S2 (3methylaminopropylamino)propy
lphosphorothioate (WR151327), were synthesized
later [10]. Phosphorylated aminothiols, such as WR
1065 (2 (3aminopropylamino)ethanethiol), WR
151326 (3 (3methylaminopropylamino)propaneth
iol), and others, were synthesized as well and proved to
be even more efficient. Notably, phosphorothioates
are toxic and the semilethal doses (LD50) of these
compounds are rather low (100 mg/kg for dogs and up
to 1.4 mg/kg for humans); the side effects of these sub
stances include nausea, vomiting, hypotension, local
tissue damage, and others [4]. All of the above named
compounds are water soluble and thus are amenable
for convenient administration; however, they are
unstable in aqueous solutions; therefore, prolonged
storage of solutions is impossible and a dosage form for
use in case of disasters has not been developed yet.
Aminoethylisothiourea (AET, Difetur) was synthe
sized in the early 1950s [11]. Investigation of the radio
protective properties of this substance demonstrated
the extreme importance of structural characteristics
for the protective efficiency of sulfhydryl compounds.
A large number of thiols, including diethyldithiocar
bamate (DDC), mercaptopropionylglycine (MPG),
Nacetylcysteine (NAC), 2mercaptoethane sul
fonate (Mesna), and cystamine, have been investi
gated. Administration of these compounds prior to
exposure to ionizing radiation was shown to have a
weaker protective effect than administration of phos
phorothioates, but the toxicity of thiols was lower as
well. Nacetylcysteine showed the lowest toxicity
when a group of compounds that included amifostine,
cysteamine, and diethyldithiocarbanate was tested on
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animals [12]. The protective effect of aminothiols was

more pronounced if they were administered shortly
(1030 min) before exposure to radiation; in this case
the protective effect of a single dose persisted for
approximately 5 h.
Cysteamine (2mercaptoethylamine, mercamine,
2aminoethanethiol) and its derivatives are used for the
prevention and treatment of radiation sickness. Cys
teamine is used as a reference substance for evaluating
the efficiency of novel radioprotective agents. Cys
teamine salts (hydrobromide, hydrochloride, ascor
bate, and nicotinate), as well as bis(aminoethyl)
disulfide dihydrochloride [13], are the least toxic and
the most efficient among the preparations of this
group.
Cystamine (bis(aminoethyl) disulfide dihydro
chloride) is a member of the aminothiol group. The
cystamine molecule can be regarded as a double mer
camine molecule with sulfhydryl groups (SH) that
are replaced by a disulfide bond (SS). The preven
tion and alleviation of a reaction to exposure to a high
dose of ionizing radiation was observed when cysteam
ine was administered prior to irradiation. The protec
tive effect of cystamine persists for up to 5 h, but the
administration of this substance after the emergence
of radiation sickness (with considerable leukopenia)
has no therapeutic effect [14].
Elimination of shortlived reactive oxygen species
that formed as a result of exposure to ionizing radia
tion is one of the mechanisms that underlie the action
of sulfhydryl (RSH) radioprotectors. These radiopro
tective compounds serve as hydrogen donors in reac
tions with oxygen or biomolecule radicals (X) [16]:
2RSH + 2OH RSSR + 2H2O or 2RSH + 2X
RSSR + 2XH. Chemical or biochemical consumption
of oxygen is known to evoke hypoxia in cells and tis
sues. Sulfhydryl radioprotectors can react with molec
ular oxygen, and iron ions (Fe3+) can catalyze this oxi
dation reaction [16]: 2RSH + O2 RSSR + H2O2.
Radioprotectors can also interact with biological mac
romolecules, such as DNA, preventing radiation dam
age to these molecules. For example, the radioprotec
tive properties of cystamine, guanidoethylsulfide, and
glutathione disulfide are due to the ability of these sub
stances to bind and stabilize DNA molecules.
The radioprotective activities of a wide variety of
thiols (RSH, R'SH, etc.) is correlated to the rate of
disulfide (RSSR') formation [15]. Regeneration of
native proteins may occur upon thiol disulfide
exchange with glutathione. This process may be cata
lyzed by thioltransferase and followed by redox reac
tions in the glutathione system connected to glu
tathione reductase and NADPH:
ProteinSSR ProteinS + SR,
RSH + R'SSR' RSSR'+ R'SH,
RSSR'+ RSH RSSR + R'SH.

662

GUDKOV et al.

However, the disulfide hypothesis provides an

explanation for the protection of proteins, but not for
that of nucleic acids, since SH groups are found in
proteins only. The protective effect of phosphorothio
ates is currently assumed to be associated with redox
signaling, namely, with the regulation of transcription
factor function [16].
LOW AND HIGHMOLECULAR
WEIGHT ANTIOXIDANTS
The active search for nonsulfide compounds with
pronounced antiradical properties started about
60 years ago, concurrently with the research on sulfhy
dryl radioprotectors [17]. A wide variety of substances,
including certain aliphatic alcohols (for example, eth
anol), propylene glycol, glycerol, and others that are
capable of trapping free radicals were investigated. The
radioprotective effects of a range of organic acids were
studied along with the effects of aliphatic alcohols.
These studies are currently only of historical interest,
since the abovenamed compounds are highly toxic
and incapable of providing efficient protection from
radiation [2]. A Nature paper that was published by
Weil et al. in 1968 [18] marked a breakthrough in this
research area, since the antioxidant properties of sta
ble synthetic nitroxides and the potential of these sub
stances as radioprotective agents were demonstrated in
the study. More recent in vitro and in vivo experiments
with nitroxides readily soluble in water showed that
administration of these compounds prior to exposure
to ionizing radiation was necessary for the manifesta
tion of the radioprotective properties [19]. Free radical
scavenging and induction of hypotension and hypoxia
in the bone marrow account for the protective action
of these compounds [2]. Aerosol formulations of GS
nitroxides are used for the therapy of radiation
induced esophagitis [16]. A large number of synthetic
antioxidants that are capable of protecting mammals
from the pathological consequences of exposure to
ionizing radiation are currently known; this group of
pharmaceuticals includes ionol, thiophane, probucol,
succinobucol, fridox, olifen, Nacyldihydroalanine,
and others [20].
The discovery of superoxide dismutase (SOD), an
antioxidant enzyme, occurred in 1969, approximately
at the same time as synthetic antioxidants started to
appear. The first report on the radioprotective effect of
CuZnSOD, a highmolecular weight antioxidant,
was published 5 years later by Petkau and Chelack
[21], who actively promoted the use of SOD in radio
biology. Radioprotective properties are now known to
be characteristic of all forms of SOD. This enzyme is
capable of eliminating oral cavity mucositis and allevi
ating lung fibrosis [22] if administered prior to irradia
tion or shortly after it. Glutathionedependent
enzymes, catalase, and combinations of these
enzymes can be used along with SOD as radioprotec
tive preparations [23].

Vitamins constitute an additional group of low

molecularweight antioxidants. The beginning of the
use of vitamins as radioprotectors dates back to rela
tively recent times, as one of the first reports dedicated
to the radioprotective properties of vitamin E [24] was
published in 1975. Compounds of this group are sup
posed to shift the balance between endogenous
radioprotective agents (biogenic amines and compo
nents of the antioxidant system) and radiosensitizers
(lipid peroxidation products) towards the predomina
tion of the former. The immunotropic activity of vita
mins, especially their stimulatory effects on the com
ponents of the nonspecific resistance system (mono
nuclear and polymorphonuclear phagocytes,
complement, interferons, lysosomes, and others) is
thought to make a considerable contribution to the
radioprotective action of this group of compounds [2].
Stress, repair, and other similar processes are accom
panied by increased metabolic demand for vitamins
for the maintenance or the required rate of metabolic
reactions, including biosynthetic processes of an
adaptive nature [3]. For example, prolonged low
intensity irradiation may trigger radiationrelated oxi
dative stress accompanied by exhaustion of the antiox
idant system. The use of water or lipidsoluble natural
antioxidants can be regarded as substrate therapy
that compensates for the lack of antioxidants in this
case [2].
ANGIOTENSINICONVERTING
ENZYME INHIBITORS
Inhibitors of angiotensinIconverting enzyme
(ACE) were originally used in cardiovascular medicine
for the treatment and prevention of cardiac insuffi
ciency; later they were applied to the treatment of
renal insufficiency as well. The therapeutic effect of
these compounds is due to the inhibition of ACE,
which converts the biologically inactive angiotensin I
into the vasoconstrictor hormone angiotensin II. ACE
inhibitors have been shown to slow down the break
down of bradykinin (a strong vasodilator) and affect
collagen synthesis [25]. The efficiency of ACE inhibi
tors and blockers of angiotensin II receptors for the
treatment of radiationinduced lung and kidney inju
ries was demonstrated approximately 2 decades ago
[26]. Notably, ACE inhibitors are usually introduced
into the body after exposure to ionizing radiation and
therefore can be classified as mitigators and therapeu
tic agents. ACE inhibitors that are currently in use
include captopril, penicillamine, pentoxifylline, elan
opril, and others. Captopril (mercapto2methylD
3propanolLproline), which is widely used as an
antihypertensive drug [27], was shown to have a con
siderable normalizing effect on the early reaction of rat
lung to irradiation [26]. The therapeutic effect of cap
topril can be to some extent attributed to the preven
tion of an ionizing radiationinduced increase in pul
monary arterial pressure that results in lung edema.
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663

Penicillamine is a weak inhibitor of angiotensinI

converting enzyme, but this compound possesses
strong antifibrotic properties and can suppress inflam
mation [28]. The use of ACE inhibitors and angio
tensin receptor blockers opens up new treatment pos
sibilities in the case of radiotherapy that requires high
radiation doses and allows for the elimination of side
effects. However, the effect of these pharmaceuticals is
tissue specific and the protection does not extend to
the gastrointestinal tract [29].

feron alpha) 24 h after exposure. The therapeutic

effect consists in the stimulation of hematopoiesis and
protection of hematopoietic organs from the effects of
exposure to ionizing radiation [36]. Acidic and basic
fibroblast growth factors (FGF 1 and FGF 2) and vas
cular endothelial growth factor (VEGF) reduce both
the severity of gastrointestinal syndrome and mortal
ity in irradiated mice.

IMMUNOMODULATORS AND CYTOKINES

The radioprotective effect of prostaglandins was

first reported in 1972 [37]. Prostaglandin E2, dilpros
taglandin E2, and OK432, an analogue of the latter,
were shown to protect mice from damage induced by
ionizing radiation [16]. Prostaglandins are normally
synthesized in nearly all tissues in response to various
effects (hormones, trauma, inflammation, or allergic
reaction), and modulate several cell functions that are
associated with normal and pathological conditions
[38]. Prostaglandins have a radioprotective effect on a
range of tissues, including the gastrointestinal tract,
bone marrow, and hair follicles. Protection from the
effects of radiation occurs only in case of prostaglan
din administration prior to irradiation (DMF < 1.3).
The principal mechanism that underlies the action of
prostaglandins is apparently related to the stimulation
of cell resistance and local regulation of biological
processes. Clinical use of prostaglandins is limited
because they cause numerous side effects, as they act
as mediators of inflammatory processes [39].

A number of studies have shown that preventive

and early therapeutic administration of immunomod
ulators alleviates radiationinduced damage consider
ably. Bacterial endotoxins (lipopolysaccharides) were
among the first immunomodulators to be investigated;
the studies of these compounds were initiated half a
century ago. Administration of these compounds
before, and in some cases even after, exposure to ion
izing radiation had a protective effect [30].
Lipopolysaccharides were also shown to protect the
intestine and bone marrow of mice from radiation
induced damage [31]. These substances were shown to
provide efficient protection from ionizing radiation (a
DMF close to 1.21.3). The polysaccharide immuno
modulators prodigiosan and translam are used in clin
ical practice [31].
Cytokines and cytokine inducers are currently of
the highest interest as potential immunomodulators
for radiation therapy. Cytokines are endogenous
mediators that are involved in the coordination and
regulation of the functioning of various cells of the
hematopoietic system. These properties of cytokines
account for the possibility of targeted modulation of
the functioning of the hematopoietic system during
the treatment of many pathological conditions,
including radiationinduced damage. Interleukin1
was the first cytokine for which radioprotective prop
erties were characterized (in 1986) [32]. Interleukin6
administered either before or after exposure to ioniz
ing radiation plays an important protective role [15].
Administration of GCSF (granulocyte colonystim
ulating factor) and GMCSF (granulocyte macroph
age colonystimulating factor) that belong to the
group of cytokines partially prevented radiation
induced damage in monkeys (DMF approximately
1.3) [33]. Both GCSF and GMCSF are used in clin
ics to restore normal neutrophil and platelet counts in
the blood after radiotherapy [34]. Recombinant
human keratinocyte growth factor (KGF), which is
marketed under the name Palifermin, confers consid
erable protection against oral mucositis in mice and
humans when administered before or shortly after
exposure to radiation [35]. Experiments with dogs and
guinea pigs that were exposed to sublethal doses of
ionizing radiation demonstrated the radioprotective
effect of repeated administration of leukinferon (inter
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PROSTAGLANDINS

METAL SALTS AND METALLOTHIONEINS

Metallothionein was discovered in 1957 during a
study aimed at isolation of proteins that are capable of
binding heavy metals [40]. The protein molecule con
tains 60 aminoacid residues, with cysteine account
ing for onethird of all of the residues [41]. Adminis
tration of metallothionein to animals protects them
from the effects of radiation. The physiological func
tion of metallothionein is believed to consist in the
protection of cells from toxic heavy metals; moreover,
metallothionein is known as an inducible protein and
its ability to be induced by a range of metal salts under
lies the radioprotective effect of this class of com
pounds [42]. Oral administration of bismuth nitrate to
mice has been shown to promote survival and reduce
the extent of radiationinduced damage to the bone
marrow of the animals. Administration of manganese
chloride and cadmium salts to mice evoked an eleva
tion of metallothionein levels in various tissues, thus
leading to increased resistance of the animals to
wholebody irradiation [42]. Metallothionein induc
tion by metal salts is organ and tissuespecific: for
example, manganese chloride administration did not
evoke an increase of metallothionein levels in the skin
and the small intestine [43]. Experiments have shown
that these compounds protect experimental animals

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from radiationinduced lethality when used at low

nontoxic concentrations (the DMF is 1.2); the effect
is primarily due to stimulation of the hematopoietic
system [42].
DNABINDING AGENTS
The radioprotective properties of Hoechst 33342
were first reported by Smith and Anderson in 1984
[44]. These properties are due to electron transfer
upon the formation of a complex of the small molecule
with DNA; therefore, the efficiency of protection can
be improved by adding an electron donor to the ligand.
Hoechst 33342 binds to the minor groove of DNA in
specific sites that contain three or four AT pairs [45].
Protection is apparently mediated by prevention of the
formation of single and doublestrand DNA breaks
(DMF is 1.3) [84]. Methylproamine is among the
DNA binding agents that are currently under investi
gation as radioprotectors [46]. The small peptide
netropsin is an efficient DNA binding agent as well,
and its radioprotective capacity is comparable to that
of Hoechst 33342 [47]. Polyamines spermine and
putrescine are nonhistone compounds that are
present in the nucleoplasm; they exhibit significant
radioprotective effects due to binding to DNA at
matrixassociated sites; thus, they prevent the forma
tion of DNAprotein cross links [48]. Chromatin
compaction and aggregation was also shown to make a
contribution to the radioprotective effect [2]. Inhibi
tors of in vivo polyamine biosynthesis are known to
have pronounced radiosensitizing effects [49].

index and are highly toxic [51]. Biogenic amines, such

as histamine, serotonin, norepinephrine, epinephrine,
and others were subsequently studied and shown to
exert a radioprotective effect by causing local hypoxia
often associated with changes in the level of NO [53].
Mexamine and indralin, two drugs that target the vas
cular system, are currently used as radioprotective
agents in clinics [1, 15]. Indralin is manufactured in
Russia under the trade name B190. This drug is an
alphaadrenomimetic that binds to postsynaptic
alpha1adrenergic receptors of the vascular wall, caus
ing smoothmuscle contraction with subsequent
hypoxia (DMF 1.31.5) [54, 55].
SELENIUM
Selenium stimulates the activity of glutathione per
oxidase, which is believed to reduce the levels of toxic
oxygencontaining products in irradiated cells and
thus to explain the radioprotective effect of selenium.
The radioprotective effect of seleniumcontaining
compounds was first reported in 1964 [56]. Selenoor
ganic compounds were later found to exhibit radiopro
tective properties only when used at moderate concen
trations, since higher concentrations of these com
pounds caused cytotoxicity [57]. Selenium can act
both as a radioprotector and a mitigator; it efficiently
alleviates the gastrointestinal syndrome. The DMF of
selenium that is administered systemically or topically
for the treatment of oral mucositis is 1.3 [2]. Selenoor
ganic compounds are thought to have considerable
potential as leading compounds for the development
of new radioprotective drugs [58].

HYPOXIAINDUCING COMPOUNDS
The ability of molecular oxygen to enhance the
effects of ionizing radiation is called the oxygen effect.
The observed difference of the radiation effects on dry
DNA and protein preparations that were irradiated in
an atmosphere of oxygen and under anoxic conditions
has interested many researchers [1]. As Gray showed
in 1953 [50], the response of cells to irradiation is also
strongly dependent on the presence of oxygen. The
coefficient of oxygen enhancement can amount to 2.8
[51]. Notwithstanding these promising results, sys
temic hypoxia achieved by inhalation of gas mixtures
with reduced oxygen content was later shown to
induce an increase of the DMF to 1.21.5, rather than
to the theoretically predicted values of 2.52.8 [52].
However, the development of hypoxiainducing radio
protective compounds continued. Attempts at induc
tion of systemic hypoxia were followed by the search
for radioprotective compounds that convert mamma
lian hemoglobin to methemoglobin and/or carboxy
hemoglobin and thus impair oxygen transport. Para
aminopropiophenol, sodium nitrite, aniline, and car
bon monoxide were tested, among others. These stud
ies are of historical interest only, since hemoglobin
modifying substances have a very low therapeutic

RNA, RNA HYDROLYZATES,

AND NUCLEOSIDES
The phenomenon of antimutagenesis was discov
ered by Novick and Szilard in 1952 [59]. RNA oligo
mers (purine ribonucleosides) were the first antimu
tagens characterized, although the mechanism that
underlies the antimutagenic activity of these mole
cules was elucidated much later. Research on the
radioprotective properties of RNA, RNA hydroly
sates, and nucleosides was initiated in the 1950s
1960s, after the discovery of antimutagenesis. RNA
preparations from yeast were shown to protect plants
and animals against radiation injury [60]. Moreover,
RNA that was administered to animals was shown to
have mitigator and radiotherapeutic effects, along
with the radioprotective effect. RNA hydrolysates that
are composed primarily of mononucleotides were
found to be as efficient as RNA [61]. Intensive
research on the radioprotective properties of inosine
was initiated in Russia in the 1990s [62]; this com
pound is now widely used in clinical practice (under
the commercial name Riboksin). Later studies showed
that a range of purine nucleosides and their deriva
tives, viz., guanosine [6365], inosine monophos
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phate [66], guanosine monophosphate [67], xan

thosine, and caffeine [68, 69] exhibit radioprotective
properties that are comparable to those of inosine. The
toxicity of all of the abovenamed compounds (except
caffeine) is low. Notably, purine nucleosides and their
derivatives possess both radioprotective (the DMF for
Riboxin (inosine) is 1.31.4) and mitigator (radio
therapic) (a DMF of 1.11.3) properties. The pro
nounced antiradical properties of purines underlie the
radioprotective effects of this class of compounds.
Several hypotheses that have been proposed to explain
the radiotherapeutic effects of purine compounds
include: (1) the effect on the activity of poly(ADP
ribose)polymerase, which is a key enzyme of DNA
repair; (2) elevated expression of repair enzymes
mediated by purine receptors A2 and A3; (3) regulation
of the mitogenactivated protein kinase signaling
pathway; (4) recovery of the depleted pool of purine
bases; and (5) elimination of longlived protein radi
cals that induce postradiation oxidative stress [69].
FULLERENES
The wide use of nanomaterials in biological
research, which was enabled by the development of
nanotechnologies, began in the last decade.
Fullerenes, which are among the most commonly
used nanomaterials, were discovered in 1985 [70]. A
paper published in Science by Krusic et al. [71]
reported the capacity of a single fullerene C60 mole
cule to bind more than ten radicals through its double
bonds and promoted the use of the name radical
sponge for fullerenes. Dendrofullerenes were shown
to provide efficient protection against radiation
induced DNA damage and cell death [72]. The effect
of fullerenols on the antioxidant system in the human
K562 erythroleukemia cell line exposed to Xrays at a
dose of 24 Gy has been reported. Supplementation of
the cell culture medium with hydroxylated fullerene
derivatives was shown to upregulate the activities of
SOD and glutathione peroxidase [73]. These experi
ments employed cell lines or aquatic organisms, while
studies on the radioprotective effect of fullerenes in
mammals are scarce. Radioprotective activity of
fullerenols of the general structure C60(OH)n that were
administered to rats at 10 and 100 mg/kg prior to irra
diation with a lethal dose of Xrays has been demon
strated. A subsequent study [75] addressed the effects
of nonmodified fullerenes and revealed radioprotec
tive effects comparable to those of C60(OH)n at sub
stance concentrations that were two orders of magni
tude lower than those used in [74]. The radioprotective
properties of dendrofullerene DF1 were reported
recently (the DMF in mammals was 1.22) [76]. The
mechanism that underlies the protective effect of
fullerenes is not completely clear, with antiradical,
membranemodifying, and other properties of these
molecules [7577] assumed to lead to the effect.
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ADSORBENTS
Irradiation of organisms following internal expo
sure to incorporated radionuclides is reportedly much
more dangerous than external exposure [2]. Radioac
tive particles that form during industrial accidents and
disasters can penetrate into animals and humans [78].
A special class of chemical compounds that are capa
ble of binding radionuclides or accelerating radionu
clide elimination from the body [16] is used to prevent
the penetration of radioactive elements, as well as their
accumulation. Polisurmin, ferrocin, vocacit, penta
cin, algisorb, pleostat, ksidifon, and others [3] were
among the first sorbents that were used to eliminate
heavy metals and radionuclides. Significant progress
in the development of heavymetal adsorbents has
been made [2].
CONCLUSIONS
The search for optimal protective substances for
use in different cases of exposure to ionizing radiation
has been going on for more than 6 decades. Early stud
ies of chemical protective agents were mainly focused
on sulfhydryl compounds, with development of novel
agents and application protocols that provide high
DMF levels as the main objective. This approach
enabled the creation of efficient radioprotective drugs,
but the severity of adverse effects often increased con
comitantly with the increase in efficiency. Thus, the
use of amifostine is currently limited to the prevention
of radiationinduced xerostomia, despite the
extremely powerful protective action of this drug.
Research on sulfhydryl compounds proceeded
towards the development of treatment strategies that
combine these agents with other drugs; several strate
gies that enable efficient protection with minimal side
effects were thus developed. Research on combined
application of multiple radioprotective agents is per
formed as well; these studies aim to harness the syner
gistic effects of drugs and minimize the potential tox
icity. Research on the radioprotective properties of
synthetic and natural antioxidants is another impor
tant area. These compounds do not provide efficient
protection upon acute irradiation, but often exhibit
antimutagenic properties. Some of the substances
that were mentioned in the present review both elimi
nate reactive oxygen species and exert a broad range of
biological and physiological effects that modulate the
bodys response to the action of ionizing radiation.
Moreover, many antioxidants and adaptogens protect
normal tissue from radiation, but do not exert a pro
tective effect on tumor tissue and therefore have con
siderable potential for use in radiation therapy that
employs radioprotective substances as well. Research
on receptormediated radioprotective interventions
has made considerable progress in the recent years.
Some of the substances that are used in these interven
tions mimic or modulate the development of infec
tious and inflammatory processes, while others act as

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GUDKOV et al.

growth factors. Thus, the present review demonstrates

the considerable progress that has been achieved in
research on radioprotective compounds and the
important contributions of Russian researchers to the
field. The review also demonstrates the necessity of
further research aimed at the development of radio
protective substances with properties that are close to
those of ideal radioprotectors.
ACKNOWLEDGMENTS
The present work was financially supported by the
Ministry of Education and Science of the Russian
Federation (agreement no. RFMEFI57814X0030)
and the Russian Foundation for Basic Research
(grants nos. 130400730a and 144403562
r_tsentr_a).
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Translated by S. Semenova