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Reviews in Cancer Biology & Therapeutics, 2007: ISBN: 978-81-7895-285-7

Editors: Usha N. Kasid, Vicente Notario, Adriana Haimovitz-Friedman and Menashe Bar-Eli

New directions in development

11 of pharmacological
countermeasures for the
acute radiation syndrome
Mark H. Whitnall and Terry C. Pellmar
Armed Forces Radiobiology Research Institute, Uniformed Services University
of the Health Sciences, Bethesda, Maryland

Abstract
Nuclear attacks and acts of radiological terrorism
have emerged as serious security threats. These
developments have increased the need to establish
safe and effective pharmacological countermeasures
that may prevent or ameliorate the effects of ionizing
radiation, to safeguard military personnel, first
responders, and civilians. Requirements include both
radioprotectants (drugs designed to block radiation-
induced damage), radiation mitigators (agents that
ameliorate the initial deleterious molecular events
Correspondence/Reprint request: Dr. Mark H. Whitnall, SRD, AFRRI, 8901 Wisconsin Ave, Bethesda, MD
20889-5603, Maryland. E-mail: whitnall@afrri.usuhs.mil
2 Mark H. Whitnall & Terry C. Pellmar

triggered by radiation) and post-radiation treatments, which are generally

designed to stimulate regeneration of injured tissue. This review focuses on the
Acute Radiation Syndrome (ARS), including the hematopoietic syndrome,
which causes death due to thrombocytopenia and neutropenia; and the
gastrointestinal (GI) syndrome, where mortality results from fluid and
electrolyte imbalance and degradation of the barrier to bacterial entry.
Current clinical practice is briefly discussed, along with possible future
strategies for pharmacological intervention. Current trends in radiation
countermeasure research focus on specific intracellular and extracellular
signaling pathways. A number of countermeasure candidates are emerging
that display significant efficacy and low toxicity.

I. Introduction
Nuclear proliferation, terrorist activity, and the distribution of nuclear and
radioactive materials make incidents involving radiation injuries increasingly
likely. There is a pressing need to develop radiation countermeasures that can
be used in the clinic for small-scale incidents, and outside the clinic in mass
casualty scenarios. This review addresses the status of countermeasures for
ARS, with particular focus on the hematopoietic and GI syndromes that result
from exposure to penetrating ionizing radiation (gamma and neutron). It does
not cover treatments for chronic or late radiation injuries such as lung fibrosis,
kidney dysfunction, or cancer or for internalized radionuclides. Medical
approaches to ARS aim to prevent or ameliorate radiation injury with
radioprotectants or radiation mitigators, or to stimulate recovery of
hematopoiesis or GI regeneration with post-radiation treatments. After decades
of work on radiation countermeasures [1-10], no pharmaceuticals are currently
approved specifically for ARS, although a few agents are approved for
symptoms of clinical radiation exposure. For example, Granulocyte Colony-
Stimulating Factor (G-CSF, or Neupogen®) mitigates radiation-induced
neutropenia. Amifostine is a well characterized radioprotectant that is used to
reduce post-radiation xerostomia in head and neck cancer patients.
Keratinocyte growth factor (KGF, palifermin or Kepivance™) is approved for
mucositis that results from radiation and/or chemotherapy. In the event of a
radiological or nuclear exposure, G-CSF and KGF might be used off-label or
through emergency use authorization but amifostine’s use is limited because of
its toxicity (nausea, vomiting, hypotension) [1].
Drug development is carried out with consideration of the context in which
an agent will be used: small-scale scenarios such as accidents will involve
post-exposure care by nurses and physicians in hospitals, with treatment
guided by some knowledge of the radiation dose received [11]. In those cases,
potential drug side effects may be acceptable, the storage conditions, expense,
administration route and schedule are not limiting factors, and extensive
Radiation countermeasures 3

medical support (e.g., antibiotics and platelet transfusions) will be available. In

a mass casualty scenario, on the other hand, significant logistical problems are
to be expected, including breakdowns in transportation, communication, and
access to medical care [12-14]. Requirements for a radiation countermeasure
will be considerably different in that situation: a drug should have extremely
low toxicity for the widest administration possible without detailed evaluation
of the extent of radiation exposure in each individual, should have a practical
administration route and schedule achievable by non-medical personnel, and
should be capable of enhancing survival in the absence of ancillary medical
support. Radioprotectants and some radiation mitigators (drugs given before
exposure) will be intended for use by small groups of first responders or
military personnel, and will have similar requirements in terms of lack of
toxicity and ease of use. In these situations, storage at environmental
temperatures would be optimal, to permit widely distributed stockpiling, and
transport in the absence of refrigeration.

II. Available radiation countermeasures

A number of reviews or manuals have been published that provide
guidance on medical management of ARS [11, 15, 16]. No drugs have been
specifically approved to treat ARS. However, drugs approved for other
indications, or drugs under Investigational New Drug (IND) status from the
FDA for ARS, can be granted Emergency Use Authorization upon approval by
the President of the United States in a radiation disaster. G-CSF and
Granulocyte-Macrophage CSF (GM-CSF) are typically used to treat radiation
accident victims off-label [11, 17-19]. Other standard measures include
antibiotics, antifungals, blood transfusions, intravenous fluids, electrolytes,
etc., in addition to antiemetic agents, antidiarrheal agents, and comfort
measures [11, 15, 17]. Platelet transfusions are necessary to treat radiation-
induced thrombocytopenia, as G-CSF and GM-CSF do not stimulate
thrombopoiesis [4]. These measures are appropriate for a hospital setting, but
one goal of current efforts is to expand the repertoire of countermeasure agents
to include drugs that do not require clinical support and physician supervision.

III. Biology of the acute radiation syndrome:

opportunities for pharmacological intervention and
previous research on radiation countermeasures
III A. Free radical scavenging or protection from direct
molecular damage
Much of the injury resulting from x- or gamma-rays results from formation
of oxygen- and nitrogen-based free radicals [20]. Although the amount of free
4 Mark H. Whitnall & Terry C. Pellmar

radicals produced directly by primary ionization events is low compared to that

produced by metabolism [21], cells respond to irradiation using amplification
mechanisms that result in continuing above-normal production of reactive
oxygen and nitrogen species [20]. A great deal of attention has been paid to
aminothiol radioprotectants capable of scavenging radiation-induced free
radicals before they can interact with macromolecules [1, 3, 6, 10].
Unfortunately, the problem of nausea and vomiting associated with the first
aminothiol radioprotectant, cysteine [22] was never overcome with later
aminothiol agents such as amifostine [1]. Nitroxides, which are free radicals
themselves, have been shown to protect cells and animals against radiation-
induced oxygen radicals [23, 24]. The use of current formulations is limited by
toxicity: nitroxides produce hypotension, reflex tachycardia, restlessness,
agitation, and seizures in mice [23]. Other free radical scavengers are also
being investigated [25]. Natural antioxidants have shown protection against
radiation lethality with less efficacy but also lower toxicity. Examples are
vitamin E-related molecules (tocols), alpha-lipoic acid, and selenium, which is
a component of the intracellular antioxidant system involving catalase and
glutathione peroxidase [6, 26-28]. A wide variety of natural products have
been studied for their radioprotective effects related to antioxidant properties
[6, 29-38], in part due to systematic efforts to characterize Ayurvedic and other
traditional Indian medicines [39]. It remains to be seen whether these products
will prove efficacious in non-rodent animal models.

III B. Initial molecular events after irradiation

A possible additional mechanism for the radioprotective effects of
sulfhydryls like amifostine (other than free radical scavenging) is immediate
repair of damage to macromolecules by hydrogen-atom donation to carbon-
centered radicals [10, 40]. The reaction is favorable because SH bonds are
generally weaker than CH bonds [10]. Although this is a post-radiation event
(occurring on the millisecond scale), a drug utilizing this mechanism of action
would be administered before irradiation.
The molecular damage caused by ionizing radiation has effects on a
variety of intracellular and extracellular signaling pathways that may or may
not promote survival of healthy cells [41, 42]. Radiation-induced reactive
oxygen and nitrogen species may cause some direct damage, but they primarily
activate intracellular pathways that can have either protective or deleterious
effects [43]. Triggering of signaling pathways may be induced by DNA
damage, free radical-sensitive transcription factors, effects of reactive oxygen
and nitrogen species on zinc and iron proteins, redox or free radical effects on
post-translational modification of proteins, and nitric oxide activation of
soluble guanylate cyclase and subsequent activation of protein kinase G [20].
The activation of damage-sensing or free radical-triggered signaling pathways
Radiation countermeasures 5

involving DNA-PK, p53, BRCA1, BRCA2, NF-kappaB (NFkB), ATM,

MAPKs, PI3K, etc., lead to cell cycle arrest, DNA repair, senescence, and cell
survival or death [41-43]. Radiation also produces rapid functional changes in
growth factor receptors such as members of the ErbB family and the TNF-α
and TGF-β receptors, which can have cytoprotective, proliferative, growth
arrest, or pro-apoptotic effects, depending on cell type and cell state [41, 44].
Injurious pro-inflammatory factors such as cytokines (induced in part by
radiation-induced activation of NFkB), chemokines, iNOS, thrombin,
histamine, and prostaglandins are produced almost immediately after
irradiation [45-58]. Modulation of these initial responses to irradiation by
radioprotectants may ameliorate radiation injury [53, 59, 60]. The cytokine IL-
4 was able to downregulate production of inflammatory mediators such as
Gro1 in plasma and lung, IL-1b in lung, and prostaglandin E(2) in colon, in
mice exposed to whole body irradiation [58].

III C. Regeneration of injured tissue

After free radical scavenging, the other classical approach to radiation
countermeasures has been the use of agents that stimulate the proliferation and
differentiation of surviving stem and progenitor cells, beginning with bacterial
endotoxins and other immunomodulators [61-63]. The radiation
countermeasure effects of these agents are now known to be largely due to
induction of cytokine expression [62]. Some agents that were first assessed
because of antioxidant properties may have radiation countermeasure effects
resulting in part from induction of cytokines, e.g., the vitamin E-related
compounds [64]. After the demonstration of radioprotective effects of
exogenously administered cytokines in rodents [2, 65, 66], the use of
hematopoietic cytokines as radiation countermeasures was extended to
nonrodent models [4, 67, 68]. A number of different cytokines have been
assessed, alone and in combination [69-81]. One approach has been to
construct hybrid synthetic cytokines designed to mimic the effects of two
different cytokines, such as G-CSF/IL-3 [77], IL-3/Mpl ligand [78], and GM-
CSF/IL-3 [80]. In addition, drugs that elevate extracellular adenosine have
been shown to synergize with G-CSF in promoting proliferation and
mobilization of hematopoietic progenitor cells [82, 83]. The primary goals of
many of these regenerative approaches have been to ameliorate radiation-
induced neutropenia and thrombocytopenia. However, members of the
fibroblast growth factor family such as FGF2, FGF20, and keratinocyte growth
factor (KGF, FGF7) stimulate regeneration of crypt cells in GI mucosa and
improve survival after total body irradiation in mice [84-89].
The advantages of the cytokines (targeting of specific receptors with
known signaling pathways) must be weighed against the toxicity associated
with their use. Although cytokines such as G-CSF and GM-CSF are considered
6 Mark H. Whitnall & Terry C. Pellmar

well-tolerated, they do have occasional severe side effects that mandate

supervision by a physician [90]. A number of other cytokines that have been
evaluated as radiation countermeasures display unacceptable toxicity [90, 91].
Cellular therapies (bone marrow transplants or stem and progenitor cell
transplants) have long been discussed in the context of recovery from radiation
injury, and have been used for some radiation accident victims [11, 92-104].
However, the results of cellular therapy in these cases have been questionable,
and the procedure requires significant medical resources. Future developments
in providing reliable, safe supplies of hematopoietic progenitors with no
immunological complications may prove useful in the case of accidents or
small scale radiological weapon scenarios.

IV. Current directions

The radiation countermeasure programs mentioned above are ongoing and
important areas of research. There is now an additional focus on small
molecules that target specific intracellular pathways that regulate cell survival,
growth, and function. Moreover, the urgency of the need has resulted in a shift
toward candidates with real prospects of advanced drug development, e.g.,
defined compounds rather than extracts, with low toxicity and practical
administration routes. Some examples of recent trends in radiation
countermeasure research are described below.

IV A. Countermeasures directed at free radical scavenging or

protection from direct molecular damage (radioprotectants)
Superoxide dismutase (SOD) helps ameliorate radiation injury by
converting the radiation-induced superoxide radical to hydrogen peroxide.
Hydrogen peroxide is disposed of by catalase or glutathione peroxidase. As
proteins, the antioxidant enzymes SOD and catalase are inconvenient to
administer as drugs. However, they have been administered in PEGylated
form intravenously as pulmonary radioprotectors in mice [105]. In those
experiments, the marked elevations of early markers of lung injury (p21, Bax,
and TGF-beta1) seen in control animals were absent after enzyme treatment,
and radiation-induced apoptosis was reduced. Another approach to elevating
levels of these enzymes that avoids the need to administer proteins involves
gene therapy. In an in vitro model of retroviral SOD gene transfer, murine
hematopoietic progenitor cells were protected from ionizing radiation as
shown by decreases in DNA fragmentation and a significant increase in
clonogenic survival [106]. An in vivo approach utilized liposomes to deliver
the SOD gene to the esophagus or to lungs in mice. Irradiation-induced
apoptosis detected in vivo in the esophagus at 5 days was decreased by the
esophageal treatment [107]. Delivery to the esophagus or by inhalation caused
Radiation countermeasures 7

increased survival in mice after thoracic irradiation [108, 109]. An alternative

pharmacological approach for increasing levels of SOD- and catalase-like
activities is the use of small-molecule mimetics [110-112]. When the SOD-
catalase mimetic EUK-189 was administered intraperitoneally shortly after
lung irradiation, DNA damage was reduced as shown by the micronucleus
assay [112]. The authors interpreted the results to mean that EUK-189 was
protecting against prolonged production of reactive oxygen species occurring
after irradiation. A recent approach has been the use of minor groove binding
ligands to ameliorate radiation-induced DNA damage [113]. It remains to be
seen whether compounds of this class with a suitable in vivo toxicity profile
will emerge.

IV B. Countermeasures directed at initial molecular events

after irradiation (radiation mitigators)
As mentioned above, free radical damage to cells after irradiation is due to
cellular amplification mechanisms that produce additional oxygen- and nitrogen-
based free radicals after the initial ionization events [20, 21]. The generation of
these reactive oxygen and nitrogen species is mediated by mitochondrial
processes related to cellular calcium homeostasis and redox regulation [20].
Calcium channel blockers such as diltiazem, which modulate entry of calcium
across the cell membrane as well as inhibiting sodium/calcium exchange in
mitochondria, have been shown to promote hematopoiesis and enhance survival
in irradiated mice at nontoxic doses [114-118].
The anti-apoptotic transcription factor NFkB is activated by and protects
against ionizing radiation, promotes synthesis of G-CSF as well as stimulating
expression of many other genes such as SOD, and also responds to cytokine
stimulation [20, 41, 42, 119-121]. It is becoming the focus of current radiation
countermeasure efforts, as exemplified by three current programs centered on
5-androstenediol (5-AED, discussed under post-radiation treatments),
truncated flagellin, and oligonucleotides expressing immunostimulatory "CpG
motifs" (CpG-ODN). With regard to the beneficial effects of these agents,
further research is needed to determine the relative importance of mitigation of
immediate damage or stimulation of regenerative processes.
Bacterial flagellin interacts with Toll-Like Receptor 5 (TLR5), which
results in activation of NFkB, cytokine induction, and stimulation of the innate
immune system [122-124]. Protectan CBLB502 is a derivative of the flagellin
secreted by Salmonella typhimurium, and injection of this compound into mice
and non-human primates enhances survival after irradiation with no associated
signs of toxicity [125, 126]. However, the non-human primate results are still
preliminary.
CpG-ODN mimic bacterial DNA and stimulate the innate immune
system by interacting with TLR9 [127]. CpG-ODN exert their
8 Mark H. Whitnall & Terry C. Pellmar

immunostimulatory effects in part via activation of NFkB [128]. Injections

of CpG-ODN into mice prior to irradiation resulted in significantly
increased 30-day survival [129]. CpG-ODN administration induced
increased levels of circulating G-CSF, IL-3, IL-6, IL-12, MCP-1, MIP-1-
gamma, and gamma interferon [130].
Genistein, a soy-derived isoflavone, is a phytoestrogen and protein
tyrosine kinase inhibitor that affects signal transduction pathways involving
Akt, FAK, ErbB-2, Bcl-2, and cytokine secretion [131]. When the compound
was injected sc 24 h before irradiation in mice, 30-day survival was
significantly elevated (Figure 1), and no adverse behavioral or pathological
effects were observed at radioprotective doses [132]. The improvement in
survival was related to accelerated leukocyte and platelet recovery and
enhanced reconstitution of multilineage hematopoietic progenitor cells in
femoral marrow [133]. Increased survival and stimulation of hematopoiesis
was also observed when genistein was administered orally for 4-7 consecutive
days before irradiation [6, 134].
Radiation-induced double strand breaks activate ATM, c-ABL, and Chk2
kinases, which phosphorylate p53 and its homolog p73, etc., resulting in
apoptosis [135]. ON01210 is a dual kinase inhibitor of Chk2 and c-ABL that
reduces radiation-induced p73 expression and apoptosis in vitro, at non-toxic
concentrations [136, 137]. This compound also produces increases in survival
in mice, at non-toxic doses, when injected prior to irradiation [138].

Figure 1. Radioprotection by genistein in mice. Mice were injected sc with genistein,

vehicle (PEG-400), or saline, 24 h before whole-body cobalt gamma irradiation (9.5
Gy). Thirty-day survival was significantly enhanced with genistein doses of 25 mg/kg
or greater (p<0.001). n = 16-48 animals/group. See also [132].
Radiation countermeasures 9

The inflammation triggered by ionizing radiation produces vascular

leakage that aggravates radiation injury, and some of the effects of cytokines
used as treatments may be due to amelioration of that leakage [139]. The
radiation-induced inflammation of capillaries is thought to result in large part
from effects on the thrombomodulin (TM)-protein C system [59, 140]. TM is
expressed on the luminal surface of endothelial cells, and interacts with
thrombin, changing it from a pro-coagulant, pro-inflammatory molecule to an
anti-coagulant. Ionizing radiation produces a deficit of TM, resulting in loss of
local vascular thrombo-resistance, and insufficient activation of protein C, an
anti-inflammatory, cytoprotective factor [59, 141]. Statins, widely used for
their cholesterol-lowering properties, strongly upregulate TM expression in
vitro [140, 142], and preliminary evidence indicates that they may ameliorate
radiation injury in vivo [59]. Pravastatin, when administered to irradiated
endothelial cells in vitro, decrease overproduction of the pro-inflammatory
cytokine IL-6, and the chemokines IL-8 and monocyte chemoattractant protein
(MCP1) [143].

IV C. Countermeasures directed at regeneration of injured

tissue (post-radiation treatments)
Although Angiotensin-converting enzyme (ACE) inhibitors have been
investigated for their effects on chronic radiation nephropathy [144], they have
also been shown to enhance acute survival and hematopoietic recovery after total
body irradiation of mice [145]. The effect was attributed to inhibition of
angiotensin II (AII) production; an angiotensin II type 1 (AT1) receptor
antagonist produced an increase in survival similar to that observed with the
ACE inhibitor [145]. On the other hand, the opposite conclusion regarding AII’s
effects was reached in a study showing that AII improved survival and
hematological recovery after total body irradiation in the same mouse strain
[146]. The reason for the discrepancy is not known. Interestingly, the ACE
inhibitor captopril ameliorated radiation injury in GI mucosa [147]. These effects
may be partly due to the free radical scavenging properties of captopril [148].
Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to
promote hematopoietic recovery in vivo [149-151]. The GI side effects of
classical NSAIDs can be avoided by using a selective cyclooxygenase 2
inhibitor, meloxicam [151]. Treatment increased numbers of granulocyte-
macrophage and erythrocyte progenitors. The effects of the NSAIDs were
shown to be due to stimulation of proliferation, not to changes in intrinsic
radiosensitivity of the cells [151].
5-AED enhances survival of irradiated mice and non-human primates with
extremely low toxicity [152-156], and stimulates production of innate immune
system cells and platelets [152-158] (Figure 2). These effects and the
stimulation of immune cell function [157] are consistent with the induction of
10 Mark H. Whitnall & Terry C. Pellmar

Figure 2. Amelioration of neutropenia and thrombocytopenia by 5-androstenediol (5-

AED) in rhesus macaques. Animals were injected im with 5-AED (n = 3) or vehicle (n
= 6), once daily for 5 days, with the first injection 3 h after whole-body cobalt gamma
irradiation (4.0 Gy). The nadirs were significantly higher, and the durations of
neutropenia and thrombocytopenia were significantly shorter, in 5-AED-treated animals
(p<0.05). Data taken from [158].

cytokines by systemic administration of 5-AED. 5-AED administration was

associated with a significant increase in serum G-CSF compared to vehicle-
treated control mice [159]. A subsequent study has shown stimulatory effects
of 5-AED on G-CSF mRNA in mouse spleen and bone marrow [160]. 5-AED-
induced gene expression was also observed for GM-CSF and other
hematopoietic cytokines (ibid.) Recently, it has been shown that 5-AED
enhances clonogenic survival of irradiated human hematopoietic progenitor
cells, and that this effect is mediated by induction of NFkB expression and
activation, and NFkB-dependent G-CSF secretion [161].
Although the radiation countermeasure efficacy of 5-AED is not due to
activation of sex steroid receptors [154], androgens have classically been used
to stimulate erythropoiesis [162]. Effects of androgens on other hematopoietic
lineages in irradiated mice have been observed [163, 164]. A recent study
showed increased survival of androgen-treated mice exposed to whole body
irradiation [165]. The anabolic steroid also ameliorated radiation-induced
thrombocytopenia and anemia in mice exposed to a sublethal dose of radiation
[165].
Current investigations of cytokines as radiation countermeasures focus on
combinations designed to stimulate recovery of multiple hematopoietic
lineages (granulocyte-macrophage, erythrocytic, thrombocytic), as well as
ameliorating damage to GI mucosa [166]. Thus the combined use of G-CSF
Radiation countermeasures 11

and erythropoietin (EPO) has been proposed, as well as thrombopoietin (TPO)

or IL-11 to enhance platelet recovery [166]. An important new direction is the
development of small-molecule mimetics of cytokines/growth factors [167].
JTZ-132 is a small molecule that stimulates proliferation of TPO-sensitive
cells, does not affect TPO-insensitive cells, and induces expression of
megakaryocyte markers in bone marrow cells [168]. When given systemically
to sublethally irradiated mice, JTZ-132 caused amelioration of radiation-
induced thrombocytopenia [168]. A related development is a rationally
designed antibody fragment that mimics TPO [169]. Small molecules or
peptides have also been reported that mimic the effects of FGF-2 [170], EPO
[171], gamma interferon [172], beta interferon [173], IL-2 [174], and IL-4
[175]. The use of such molecules may mimic the effects of cytokines in
stimulating recovery of injured tissue, with the advantages of small-molecule
pharmaceuticals in terms of safety, administration parameters, and storage and
transport logistics. In addition, small molecules that act as cytokine antagonists
may be useful in ameliorating some of the deleterious effects of inflammatory
mediators [176].

V. Conclusions
After decades of published work on radiation countermeasures, few drugs
are currently available for countering the effects of external penetrating
ionizing radiation. However, several candidates are emerging that have
significant efficacy in terms of enhancing survival after irradiation, with low
toxicity. No longer purely an academic enterprise, the field is starting to attract
resources from biotechnology companies and funding agencies with a serious
view toward developing products that can be used both within and outside a
hospital setting. Modern biological concepts are being applied to target
specific molecular responses related to direct damage by radiation and
radiation-induced free radicals, initial radiation-triggered events modulating
intracellular and extracellular signaling pathways, and regeneration of
surviving stem and progenitor cells in injured tissue.

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