Abstract
Introduction:
There is a limited array of currently available medicinals that are useful for either the prevention, mitigation or treatment of bodily injuries arising from ionizing radiation exposure.
Area covered:
In this brief article, the authors review those pharmacologic agents that either are currently being used to counter the injurious effects of radiation exposure, or those that show promise and are currently under development.
Expert opinion:
Although significant, but limited progress has been made in the development and fielding of safe and effective pharmacotherapeutics for select types of acute radiation-associated injuries, additional effort is needed to broaden the scope of drug development so that overall health risks associated with both short- and long-term injuries in various organ systems can be reduced and effectively managed. There are several promising radiation countermeasures which may gain regulatory approval from the government in the near future for use in clinical settings and in the aftermath of nuclear/radiological exposure contingencies.
Keywords: Acute radiation syndrome, chronic/delayed radiation injuries, cytokines, growth factors, irradiation, pharmacological agents, radiation countermeasures
1. Introduction
Increasing risks of radiological and nuclear accidents or terrorist attacks has driven revived interest in developing radiation countermeasures to potentially injurious exposures to radiation. Thus, radiological preparedness and development of radiation countermeasures are important security issues for not only the individual, but also for the nation at large [1]. Beyond the latter and in light of the increased use of radiotherapy, there is an ever present need to improve the types of preventive and therapeutic agents that serve to minimize collateral normal tissue injury arising from radiotherapeutic treatments. Radiation countermeasures have been grouped as radioprotectors, radiomitigators, and radiation therapeutics, based on the time of drug administration in relation to irradiation. Radioprotectors are administered before radiation exposure as prophylaxis. Radiomitigators are used soon after radiation exposure and prior to the appearance of overt symptoms to stimulate recovery. Radiation mitigators are needed for mass casualty scenarios while radioprotectors will be helpful in radiotherapy and use for soldiers in anticipation of radiation exposure. Lastly, radiation therapeutics are used once symptoms of radiation exposure manifest [2].
Radiological and nuclear threats can be classified into several groups: (a) detonation of a sophisticated nuclear weapon or nuclear bomb, (b) explosion of an improvised nuclear device, (c) use of a dirty bomb or a radiological dispersal device (RDD), (d) an attack on a nuclear power plant, (d) use of a radiological device, and (f) unintended radiological/nuclear accidents [3]. Under any large scale radiological/nuclear event, the number of people who will require medical attention will be large. The actual number (fraction) of individuals seriously affected by relatively high radiation doses within the overall exposed population is generally small; this is to say that low dose exposures would invariably affect significantly larger numbers of individuals than would extremely high, life-threatening doses of radiation affecting smaller numbers. On this point (a point we will return to later in this review), both national and global research effort on developing essential resources to counter these radiation health risks have focused largely (with expenditure of invaluable resources) on acute, potentially lethal injuries. These injuries would affect relatively few individuals compared to the chronic or delayed-type of injuries caused by lower exposure levels that would affect a larger number of individuals at risk.
The above radiation-associated injuries can be categorized in terms of ‘time’ to manifest a given injury or disease, as well as by the injury/disease’s etiological nature, namely it can be described precisely in terms of the exposed individual or the population of exposed individuals at large. On the basis of ‘time’, injuries/diseases can be described in terms of either ‘early’ or ‘late’ occurring: on the basis of providing etiological descriptions of the injury/disease in question. Injury-initiating responses are described commonly as being either ‘deterministic’ or ‘stochastic’ by nature. Incidence and severity of deterministic-type of injuries are largely the function of the total exposure ‘dose’, but also depend on exposure intensity and radiation quality. Exposure ‘thresholds’ for injury induction tend to characterize these types of responses. Early occurring blood disorders induced by radiation exposure, such as pancytopenia, are representative of this class of deterministic injury responses. By contrast, ‘stochastic-type’ radiologic injuries/diseases are probabilistic with measures of risk to incur injury/disease within the exposed population rather than to the exposed individual per se. Stochastic-types of injuries/diseases generally associate risk of injury/disease occurrence with radiological parameters and conditions (i.e., dose, dose-rate, radiation quality), but often lack clear evidence of exposure thresholds. Late arising, radiogenic cancers are considered ‘stochastic’ type of pathological responses [4]. These major ‘categorical’ descriptors of the radiogenic disease entities are used throughout the text in order to provide better context for the development and use of current and future pharamcotherapeutics.
Common forms of ionizing radiation include electromagnetic radiation (γ-rays and X-rays) and particulate radiation (a stream of atomic or subatomic particles; electrons, neutrons, protons, β-, and α-particles). The extent of ionization deposited along a track of radiation defines the magnitude of linear energy transfer (LET). γ-rays and X-rays are of low LET and characterized by sparse ionization while α-particles and neutrons are of high LET and tracks high ionization [5]. Now, it is well understood that the free radicals generated by radiolysis of cellular aqueous milieu and their interaction with one another and also with oxygen are primarily responsible for inflicting radiation injuries. Free radicals (primarily hydroxy radicals) are responsible for the indirect radiation action producing approximately 75% of low LET damage. This part may potentially be prevented by radical scavengers. By contrast, radical scavenger do not protect against damage by high-LET radiation which is produced predominantly by direct radiation action in DNA. Variation in individual’s response to radiation may be as a result of individual’s ability to detoxify radiation-induced free radicals. Such detoxification of free radicals are due to endogenous antioxidant enzymes, thiols, and various exogenous antioxidant nutrients; vitamin E, selenium, carotenoids, vitamin C, and flavonoids.
Three types of radiation induced injury can happen as a result of radiological/nuclear accident or deliberate use of radiation source to cause harm; external radiation exposure, contamination with radioactive materials, and incorporation of radioactive material (radionuclides) into the body. Usually, the higher the dose of radiation, the more severe the early effects will be and there will also be more probability for the delayed effects in exposed individuals. There are different types of syndromes based on the time of manifestation in relation to radiation exposure; acute, delayed, late, and chronic syndromes. Acute radiation syndrome (ARS) is characterized by the differential response of the body’s important organs to various doses of radiation exposure. The clinical progression of ARS depends on the tissue-absorbed radiation dose and its distribution within the body [6]. The signs and symptoms that progress during ARS occur through four different phases; prodromal, latent, illness/manifest, and recovery or death phase. Depending upon the dose of radiation and available treatment, the outcome may be survival or death. Delayed, late, and chronic effects of radiation exposure manifest in due course of time.
The intent of this article is to summarize those ‘pharmacotherapeutics’ currently available in treating the ‘radiation injured’ and highlight those types of injuries where such ‘treatments’ are presently unavailable, but under investigation. Specific medicinal needs, as well as basic radiological medical management needs are addressed as well.
2. Radiation exposure associated sub-syndromes
Though there is recent shift in the thinking, most radiation countermeasures are being developed for specific syndromes or for specific sites of tissue injury. Thus, it is important to discuss various sub-syndromes and to describe treatments and treatment modalities currently available. As stated above, ARS is the syndrome receiving the most attention, although other syndromes are also important and need equal consideration as well.
2.1. Acute radiation syndrome (ARS)
2.1.1. The hematopoietic tissue injury- hematopoietic sub-syndrome of ARS (H-ARS)
General description.
The prominent and well-studied sub-syndrome of ARS, H-ARS, manifests at the lowest level of the radiation doses that leads to acute injury. General descriptions of radiological exposure conditions and associated pathological sequences have been well documented over the past decades since the dawn of the atomic age [7,8]. It is as a result of the high radiosensitivities of committed progenitors of neutrophils and thrombocytes lineages [6,9]. Any radiation dose of 2 Gray (Gy) and above results in decreased blood cell counts and immunosuppression, leading to secondary infections. Exposure may result in hemorrhage, bone marrow (BM) failure, and/or infections. In the absence of treatment, death may occur within 2 – 8 weeks post-irradiation. Hence, protection/reconstitution of the hematopoietic system is very important [10,11].
Rates of lineage-commitment of stem cells and subsequent proliferation and differentiation of associated progenitorial cells within lymphohematopoietic tissues determine the time required for each symptom to manifest. The time until symptoms manifest, the level of the nadir based on cell count, and the recovery period (time it takes to return to baseline) for each cell lineage have been characterized as secondary endpoints to investigate the degree of hematopoietic damage. Pluripotent stem cells localized in the BM are able to survive, but with decreased probability following escalating exposures to mid-range doses (2 – 6 Gy) of ionizing radiation that result in H-ARS. However, when the dose increases, the fraction of surviving stem cells decreases and the recovery of various progenitorial blood cell lineages is delayed. Radiation countermeasures for H-ARS are largely based on the stimulation of the recovery of various hematopoietic cell lineages. The injurious effects of radiation on hematopoiesis have been well studied in various animal models [12]. The three animal models extensively used in the majority of studies are mice, canines, and nonhuman primates (NHPs). H-ARS occurs more quickly in murine model while for larger animal models such as NHP [13], a 60 d period is considered more appropriate [14].
Clinicial management.
Clinical management of the hematopoietic syndrome with its’ hemorrhage, acute anemia, and potential lethal complications of sepsis, are all related to the standard clinical protocols used for marrow hypoplasia and pancytopenia, regardless of the etiologies of those separate pathologies. Therapy would certainly encompass, but not limited to the use of antibiotics, blood, and platelet transfusions. The utility of extended platelet transfusions might be limited by the recipient’s own immune response to those subsequent transfusions. Due to the patient’s suppressed immunity and the increased susceptibility to infections, aseptic protocols must be rigidly employed.
Mitigative and therapeutic agents in clinical use (regulatory agency approved).
Three radiomitigators approved by US regulatory agency, United States Food and Drug Administration (US FDA) for H-ARS are granulocyte colony-stimulating factor (G-CSF), PEGylated G-CSF (a 20 KDa monomethoxypolyethylene glycol (PEG) molecule covalently linked to the N-terminal methionyl residue of G-CSF), and granulocyte-macrophage colony-stimulating factor(GM-CSF) (table 1) [15-18].
Table 1.
US FDA-approved growth factors for H-ARS [2]
| Growth factors | Mode of action | Indication for FDA approval and dose |
Comments | References* |
|---|---|---|---|---|
| G-CSF/filgramostim/Neupogen | Promotes proliferation, differentiation, commitment, maturation, and function of neutrophils | Adult patients of H-ARS: single daily sc injection of 10 μg/kg continuing until the ANC remains greater than 1,000/mm3 for 3 consecutive CBCs when CBC is investigated every third day. | Effective with full supportive care including individualized antibiotics and blood transfusion in large animal model, administration can be delayed up until 24 h after radiation exposure | [15,23,25] |
| PEGylated G-CSF/PEGylated filgramostim/Neulasta | Promotes neutrophil proliferation, differentiation, commitment, maturation, and function | Adult and pediatric patients of H-ARS: two doses of 6 mg each, administered sc one week apart. For pediatric patients <10 kg: 0.1 mg/kg; 10 – 20 kg: 1.5 mg; 21 – 30 kg: 2.5 mg; 31 – 44 kg: 4 mg. The first dose administered as soon as possible after radiation exposure. | Effective with full supportive care including individualized antibiotics and blood transfusion in large animal model, administration can be delayed up until 24 h after radiation exposure | [18,31] |
| GM-CSF/Sargramostim/Leukine | Supports granulocyte-macrophage lineage (neutrophils, monocytes/macrophages and derived dendritic cells) and hematopoietic progenitors | Adult and pediatric patients of H-ARS: single daily sc injection: 7 μg/kg in adult and pediatric patients weighing >40 kg, 10 μg/kg in pediatric patients weighing 15 – 40 kg, 12 μg/kg in pediatric patients weighing <15 kg until the ANC remains greater than 1,000/mm3 for three consecutive CBCs when CBC is investigated every third day. | Effective with minimal supportive care without individualized antibiotics and blood transfusion in large animal model, administration can be delayed as long as 48 h after radiation exposure | [16,37,39] |
G-CSF/filgrastim/Neupogen.
The radiomitigative efficacy of G-CSF has been demonstrated in different strains of experimental animals: mice, canines (beagle), minipigs [19], and NHPs [2,19-21]. Because G-CSF is not species-specific like GM-CSF, a majority of these studies have been accomplished using human recombinant G-CSF. G-CSF enhanced survival rate and blood neutrophil recovery across several animal species against various radiation sources (γ-ray and X-ray). In addition, G-CSF has been shown to be a radiomitigator against mixed field (neutron and γ-photon) in mice [22]. G-CSF has also been used in several accidents to treat radiation-exposed victims with significant benefits [21]. In March 2015, G-CSF was approved by the US FDA to treat adult humans for H-ARS [15,23]. This approval was based on its radiomitigative efficacy in NHPs following Animal Rule. The FDA Animal Rule states that the approval of a drug to treat or prevent a life-threatening illness triggered by a permanently disabling or lethal agent can be granted, if animal efficacy studies satisfactorily corroborate that the drug under investigation will yield a clinical advantage [24].
The recommended dose of Neupogen is 10 μg/kg as a single daily subcutaneous (sc) injection for individuals exposed to radiation doses of > 2 Gy (myelosuppressive dose) as soon as possible after exposure to radiation, and should be continued until the absolute neutrophil count remains greater than 1,000/mm3 for 3 consecutive complete blood counts (CBCs) when CBC is investigated every third day [25]. The treatment plans for radiation-exposed victims in a radiological/nuclear event, the stability of G-CSF at ambient temperature, and its effects on radiation-induced lung injury are some issues of concern [26]. Pivotal G-CSF studies in NHPs which led to its FDA approval have used intensive supportive care including blood transfusion and individualized antibiotics. In a mass casualty scenario, capability for such treatments will be constrained [20]. Additional issues are its side effects which include fever, hypoxia, myalgia, respiratory distress, sickle cell crisis, splenomegaly, and Sweet’s syndrome [27]. G-CSF administration is also associated with delayed platelet recovery in treated victims [28]. WHO strongly endorsed G-CSF administration within 24 h to victims exposed to >2 Gy dose [29].
PEGylated G-CSF/ PEGylated filgrastim/Neulasta.
PEGylated G-CSF (PEGfilgrastim: Neulasta) is a sustained-duration form of filgrastim with a 20 KDa monomethoxypolyethylene glycol molecule covalently linked to the N-terminal methionyl residue [17]. The activity and mechanism of action of the PEGylated and non-PEGylated forms of G-CSF are similar [30]. Prior to its approval for H-ARS, Neulasta had FDA approval for several indications [31]. In November 2015, it received FDA approval for increasing survival in patients acutely exposed to myelosuppressive doses of radiation (>2 Gy) inducing H-ARS [18,31,32].
PEGylated G-CSF has well-documented radiomitigative potential against potentialy lethal radiation exposures in both mice and NHPs, similar to G-CSF [32,33]. Two weekly injections of PEGylated G-CSF are equivalent to or significantly better than 17 – 21 daily injections of G-CSF [32,34]. It has also been shown that PEGylated G-CSF restricts the severity of the radiation-induced ARS cytopenias in the rodent model. However, Neulasta appears to be less efficacious than G-CSF in treating combined injury with irradiation and skin burns in murine model (irradiation and 15% total-body surface area skin burns) [35]. Neulasta treatment has also been investigated after proton radiation exposure in experimental animal model. Minipigs (Yucatan) exposed to total-body proton irradiation at a dose of 2 Gy received 4 treatments of Neulasta (0.1 mg/kg, sc on day 4, 7, 10 and 13 post-irradiation). Neulasta significantly improved white blood cells, specifically neutrophil, compared with the vehicle control group of animals [36]. Neulasta was approved by the FDA based NHP study conducted with full supportive care (blood transfusion and use of individualized antibiotics) following Animal Rule [32].
The recommended dose of Neulasta is two doses of 6 mg each, administered sc one week apart. For pediatric patients weighing less than 45 kg, recommended doses are: <10 kg: 0.1 mg/kg; 10 – 20 kg: 1.5 mg; 21 – 30 kg: 2.5 mg; 31 – 44 kg: 4 mg. It is recommended to administer the first dose as soon as possible after suspected or confirmed exposure to >2 Gy radiation dose. Similar to G-CSF and GM-CSF, PEGylated G-CSF has also been used in several radiation accident victims with encouraging results [21,27].
GM-CSF/Sargramostim/Leukine.
Leukine received FDA approval as a radiomitigator to treat adult as well as pediatric patients for H-ARS in March 2018 [16,37]. The use of Leukine to treat neutropenia in clinical settings supported its use in victims exposed to non-therapeutic doses of ionizing radiation. GM-CSF has been used to treat radiation-exposed victims in several accidents in various countries [21,27,38,39].
The efficacy of Leukine was investigated in a number of preclinical large and small experimental animal models. The radiomitigative potential of GM-CSF has been demonstrated in rodents, canines, and NHPs [21,39]. In addition to the native form of GM-CSF, several recombinant forms of GM-CSF have been investigated in experimental animal models. Some of these agents are regramostim (mammalian cell expressed), molgramostim (bacterial), and sargramostim (yeast) [21]. Molgramostim and sargramostim have been used in humans. Since two repeat arginines (positions 22 and 23) triggers the yeast to produce a protease, the arginine at position 23 has been replaced with leucine in sargramostim. Sargramostim binds to the GM-CSF receptor of humans, NHPs, and canines but does not cross-react with the receptor in rodent and swine models. Species specificity may be responsible for failure to observe efficacy of GM-CSF in some studies [40,41].
Sargramostim was investigated as a radiomitigator in NHPs and was found to significantly improve survival benefit when administered 48 h post-exposure at a dose of 7 μg/kg/day, sc (number of doses depended on neutrophil counts in irradiated NHPs) with minimal supportive care (single antibiotic (Baytril) and no blood products) against two different doses of radiation (6.55 Gy (LD50-60/60) and 7.13 Gy (LD70-80/60)) [42]. In the 6.55 Gy radiation dose group, survival was improved by 36% (p = 0.0018) and in the 7.13 Gy dose group, survival was enhanced by 44% (p = 0.0076). In treated groups, sargramostim accelerated the time to neutropenia and thrombocytopenia recovery and decreased infection rates (personal communication: Debasish Roychowdhury, Partner Therapeutics, Lexington, MA, USA). This study formed the basis of FDA’s approval of Leukine under the FDA’s ‘Animal Rule’ for treatment of H-ARS [16,37]. It can be administered as late as 48 h after radiation exposure, while Neupogen and Neulasta need to be administered by 24 h post-exposure for their optimal efficacy. It is important to note that G-CSF was not effective when evaluated in the absence of full supportive care (blood products) [43] but GM-CSF was found to be effective without the use of blood products and individualized antibiotics (based on bacterial sensitivity) [42]. Unpublished data suggest that sargramostim use can be further delayed beyond 48 h post-irradiation (personal communication: Dr. Debasish Roychowdhury, Partner Therapeutics, Lexington, MA, USA). Storage of sargramostim in powder form at ambient temperature is additional positive attribute of this radiomitigator.
The recommended dose of Leukine for patients with H-ARS is a sc injection administered once daily as follows: 7 μg/kg in adult and pediatric patients weighing greater than 40 kg; 10 μg/kg in pediatric patients weighing 15 kg to 40 kg; 12 μg/kg in pediatric patients weighing less than 15 kg. Leukine should be administered as soon as possible after radiation exposure to >2 Gy [37]. It is recommended to obtain a baseline CBC and then serial CBCs every third day until the absolute neutrophil count (ANC) remains greater than 1,000/mm3 for three consecutive CBCs.
Promising new prophylactic, mitigative/therapeutic agents currently under preclinical evaluation.
There are a large number of agents under development and it is not possible to discuss all those agents due to limitation of space in this article. Only few agents with recent work are briefly discussed below. Readers may like to go through recent comprehensive review articles for information regarding other agents, particularly agents having FDA investigational new drug (IND) status for ARS (table 2) [2,44,45].
Table 2.
Radiation countermeasures for ARS with US FDA IND status [24]
| Biologics | Mode of action | Animal models of radiation injury used |
Comments |
|---|---|---|---|
| AEOL 10150 | Neutralizes reactive oxygen and nitrogen spices | Efficacy for DEARE in rodent and large animal models | Safe and well tolerated in phase 1 study |
| CLT-008 | Produces granulocytes, red blood cells, and platelets | Radiomitigative efficacy in different strains of mice | Completed phase 1 safety testing |
| BIO 300 | Antioxidant, anti-proliferation, anti-cancer | Effective in rodent, being tested in large animal model | Safe and well tolerated in clinical study |
| Entolimod | NF-κB activator, immunomodulator, free radical scavenger, stimulates cytokine production | Studied in murine, canine, and NHP models | Safe and well tolerated in clinical study |
| HemaMax | Promotes Th1 maturation, may activate NF-κB activator, T cell-activating factor | Investigated in mice and NHPs | Safe and well tolerated in clinical study |
| Neumune | Promoted hematopoiesis, ameliorates neutropenia, activates immune cells | Tested in mice and NHPs | Safe and well tolerated in clinical study |
| OrbeShield | Modulates local inflammation and epithelial cellular apoptosis in GI | Radiomitigative efficacy observed in canine | Safe, no effect on bone metabolism (a common issue with steroid administration) |
| PLX-R18 | Releases cytokines, chemokines, and growth factors | Effective in mice and NHPs | Clinical study has not yet been reported |
| Recilib | Upregulates PI3-kinase/AKT pathways, potentiate DNA repair | Studied in small and large animal models | Safe and well tolerated in clinical study |
Genistein/BIO 300.
Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one) is an isoflavone derived from soy, has two open FDA INDs for the indications of H-ARS as well as delayed effects of acute radiation exposure (DEARE). Genistein is a selective estrogen receptor agonist, protein tyrosine kinase inhibitor, antioxidant, and free radical scavenger [46-49]. The molecular structure of genistein closely resembles estrogen, allowing it to act as an agonist of all estrogen-binding receptors. There are two estrogen responsive cellular receptors that function as transcription factors; estrogen receptor-α (ERα) and estrogen receptor-β (ERβ) [50]. Although genistein binds to both ERs, it binds ERβ with a ~20-fold greater affinity than ERα [51].
Genistein can act as a radioprotector and also as a radiomitigator. BIO 300 is an aqueous suspension consisting of synthetic genistein nanoparticles that is manufactured using a proprietary nanomilling process. This formulation has several key advantages including improved bioavailability and ease of administration. Supporting experiments were executed with either genistein or BIO 300. Initial nonclinical research carried out using murine models established genistein’s radioprotective efficacy [52]. When administered via the sc route of administration 24 – 12 h prior to total-body irradiation (TBI, 9.25 Gy 60Co γ-radiation), a single dose of BIO 300 significantly improved 30 d survival in a murine model[53]. A single intramuscular (im) injection of BIO 300 was an effective radioprotectant when given prophylactically 48 h to 12 h before 9.25 Gy irradiation, with optimal efficacy when administered 24 h before irradiation. The dose reduction factor of the BIO 300 as a radioprotector was 1.16 [54].
Another study demonstrated that twice daily oral (po) administration of BIO 300, initiating 6 days prior to TBI (8.75 Gy 60Co γ-radiation), significantly improved 30 d survival in mice (personal communication - Michael Kaytor, Humanetics Corporation). BIO 300 underwent further development as a radiomitigator for ARS and DEARE [55].
Recently, the pharmacokinetics and safety of BIO 300 has been assessed in NHPs. In this study, two routes of BIO 300 administration were analyzed: po and im injection. Serum samples from animals receiving a single dose of BIO 300 were analyzed for global metabolomic changes using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS). Transient alterations in phenylalanine, tyrosine, glycerophosphocholine, and glycerophosphoserine were observed which reverted back to near-normal levels 7 days after drug administration [56]. A significant overlap in the metabolite profile induced by each route of administration was found; with the po route showing fewer overall metabolic alterations.
Human Phase 1 (IND 74460) for safety and pharmacokinetics as well as Phase 1b/2a (IND 119322) for BIO 300 have been completed with no dose limiting toxicities (personal communication - Michael Kaytor, Humanetics Corporation). Of note, genistein used as a mitigator has been reported to reduce adverse effects of chemotherapy and radiotherapy in clinical trials [57,58].
Placental-derived cellular therapy (PLXR-18).
PLX-R18 cells are 3D-expanded placenta-derived cells with the ability to protect and regenerate BM. These cells secrete several cytokines including G-CSF, interleukin-6 (IL-6), monocyte chemoattractant protein-1, and growth regulated oncogene (GRO), also known as keratinocyte chemoattractant (KC) which participate in the reconstitution of hematopoietic system and provided survival benefit in irradiated C3H/HeN mice [59,60]. PLX-R18 helps in recovery of white blood cells, red blood cells, and platelets in irradiated animals. C3H/HeN mice were exposed to 7.7 Gy TBI with linear accelerator (LINAC). On days 1 and 5 after irradiation, two million cells from different preparations of human derived 3D expanded adherent placental stromal cells (PLX) were administered im [61]. Treatment with pure maternal cell (PLX-Mat) as well as with a mixture of maternal and fetal derived cells (PLX-RAD) increased the survival of the irradiated mice. The dose modifying factor (the relative dose of radiation required for a given effect (e.g. 50% lethality during a specific period) in the drug-treated group as compared with radiation-only control group) was approximately 1.23. Initiation of the treatment with PLX-RAD could be delayed up to 48 h after irradiation. A faster recovery of the BM in the PLX-RAD treated animals supports the increased survival of the cells-treated and irradiated mice. Recently, this agent has been demonstrated to protect mice against γ-radiation when administered prior to irradiation [62]. This agent has been granted orphan drug status by the FDA. In unirradiated animals, these cells do not increase CBCs in recipient animals suggesting that this agent can be given to radiation exposed victims without assessing the radiation dose. It received FDA IND status for ARS in April 2018 [63]. PLX-R18 efficacy was also investigated in irradiated NHPs administered as an im injection. Though the sample size in the NHP study was small (six or seven NHPs/group), all PLX-R18-treated NHP groups (three doses; 4, 10, and 20 million cells/kg) demonstrated improved survival compared to untreated group where mortality was 50% [64]. This study suggests that im treatment with PLX-RAD may be an effective ‘off the shelf’ therapy to treat BM failure following irradiation.
Thrombopoietin (TPO).
TPO and related analogs are generally considered as potential mitigators or therapeutics in managing acute radiation injuries. TPO was used and shown to have therapeutic value in radiation accident victims of Tokai-mura, Japan [65]. TPO has been shown to increase survival and hematopoietic recovery in irradiated C57BL/6J mice when administered (0.3 μg/mice) either 2 h prior or 2 h after γ-irradiation [66,67]. Romiplostim (Nplate) is a synthetic TPO agonist which targets the TPO c-Mpl receptor and stimulates preferentially platelet generation within the BM [68,69]. The agent is the first FDA-approved thrombopoiesis-stimulating protein for the treatment of low platelet counts in adults with chronic immune thrombocytopenia (idiopathic thrombocytopenia purpura, ITP). Romiplostim is being developed as a radiation countermeasure for H-ARS by Amgen.
A single intraperitoneal (ip) administration of Romiplostim initiated 2 h after irradiation and continued for 3 or 5 d (daily administration, 50 μg/kg) provided 100% survival in C57BL/6J mice exposed to a lethal dose (7 Gy, dose rate 0.9 Gy/min) of Cesium-137 (137Cs) γ-rays [70]. By day 30, the peripheral blood cells, BM cells, and haematopoietic progenitor cells of the Romiplostim administered irradiated mice recovered to a level that was not significantly different from unirradiated mice. In a recent study, Romiplostim administration to lethally irradiated mice increased survival, promoted hematopoiesis in multiple organs, and reduced injury to tissues. Furthermore, Romiplostim suppressed the expression of several microRNAs known to be associated with radiation induced leukemogenesis [71]. In another study, maximal survival enhancement of ∼40% was achieved after a single 30 μg/kg dose of Romiplostim [72]. Administration of PEGfilgrastim and Romiplostim or the combination of both agents resulted in improvements in hematological parameters compared with irradiated control NHPs [73]. The most hematologic advantage in respect of platelet and neutrophil was noted when PEGfilgrastim and Romiplostim were dispensed as a combination therapy. These effects demonstrate that Romiplostim alone or in combination with PEGfilgrastim is helpful in improving hematological recovery in irradiated NHPs. These results support further development of Romiplostim as a medical countermeasure to improve primary hemostasis and survival in ARS. A phase II clinical trial for efficacy has been completed for chemotherapy-induced thrombocytopenia for which this agent is used off-label [74].
Similar to Romiplostim, Eltrombopag (Promacta) is another mimetic of TPO/agonist of TPO receptor, and this agent is FDA-approved for three indications: ITP, thrombocytopenia in patients with chronic hepatitis C, and aplastic anemia. It is a synthetic TPO receptor agonist discovered by Ligand Pharmaceuticals and developed by GlaxoSmithKline (GSK), and now marketed by Novartis. It is orally effective (bioavailability 52%), has a long half-life, and a four-year shelf-life. It promotes development of megakaryocytes and increases platelet count. Eltrombopag has been shown to increase up to 100% platelet counts in chimpanzees when administered po at a dose of 10 mg/kg/d for five days [75]. Since it is effective only in humans and chimpanzees, its developmental path is complicated as chimpanzees cannot be easily used as an animal model for its development as a radiation countermeasure.
2.1.1.1. Agents approved for other limited clinical indications
Amifostine is the only agent classified as a cytoprotectant and is approved for narrow clinical indications associated with radiotherapy and chemotherapy [76,77]. Furthermore, there are several cytokines and growth factors (palifermin (keratinocyte growth factor), erythropoietin (Epoetin/Epogen/Procrit/Darbepoetin/Aransep), IL-3, IL-11 (Oprelvekin)) which have been approved by the FDA for limited indications (mostly cancer patients receiving chemotherapy and/or radiotherapy) [2,44,45].
2.1.2. Gastrointestinal tissue injury, the sub-syndrome of ARS (GI-ARS)
General description.
The GI tract is particularly sensitive to radiation exposure and GI-ARS occurs as a result of several sequential and pathophysiological events. Other constituents of the GI tract also add to system dysfunction and the ultimate outcome is the death of clonogenic crypt epithelial stem cells [78]. The vital event in the pathophysiology of GI injury is enterocyte loss and vascular injury contributing significantly at higher radiation doses [79]. Although vascular injury may play a role in the GI syndrome, it is the loss of 4 – 6 stem cells near the bottom of the crypts that eventually cause the breakdown of the intestinal lining and death within 7 – 10 days. The physiological symptoms involve nausea, vomiting and diarrhea, which are GI-related symptoms of irradiation. Clinical studies have shown that individuals receiving whole-body or upper-abdominal irradiation often display nausea, vomiting, and retching as side effects. These symptoms aggravate electrolyte and fluid loss and ultimately lead to morbidity/mortality [6]. With an extended period following radiation exposure, considerable tissue restoration occurs as a result of the initial radiation-induced injury and helps to change the gut structure, motility, and absorption potential. Fibrosis makes recovery more difficult because it makes tissue more susceptible to adhesions, perforation, and stenosis [80]. It is important to note that neither radioprotectors nor mitigators are available for GI-ARS.
Clinical management.
Because radiation-induced injury of GI tract is not an infrequent side effect of radiotherapy, a considerable proportion of patients suffer either acute or chronic GI symptoms. As a result, rather standard clinical management protocols have been developed and are currently being applied. Agents that constitute these protocols include: anti-emetics and mild sedatives along with infusions of fluids, electrolytes, and plasma; the latter of which are dictated by clinical condition and blood chemistries (especially electrolytes and proteins), blood pressure, pulse, urine output, and skin turgor.
Mitigative and therapeutic agents in clinical use (regulatory agency approved).
Although specific biological, chemical and pharmacologic agents have been long sought in attempting to manage radiation-induced injury, still to date there are no clearly-proven, safe, and effective agents currently available. The latter is stated despite the promising initial, preclinical research findings suggesting the utility of nutritional-based interventions proved to be not significantly effective [81]. Nevertheless, some researchers have suggested that treatments involving probiotic supplements, low fat diet, and elemental diet need further evaluations [82,83]. It should be noted however that ‘preventive’ approaches have been applied clinically in order to minimize GI injury following acute irradiation. Amifostine, a well-studied radioprotectant mitigates injury by a scavenging tissue-toxic reactive oxygen species, while sucralfate (sucralfate (aluminium sucrose octasulfate) protects the mucosal cell lining of the gut by still ill-defined process(es) [84,85]. Rectal administration of amifostine (two daily 1g doses) prior to radiation therapy for prostate cancer has been reported to significantly improve quality of bowel movements and, consequently, the so-called ‘quality of life’ toxicity parameters associated with the radiotherapeutic protocols [84]. Again, the beneficial effect of sucralfate treatments prior to radiotherapy appears to relate to improved bowel functions (i.e., frequency of defecation and stool consistency) [85].
Promising new preventive/mitigative agents currently under preclinical evaluation.
A comprehensive listing of mitigative/therapeutic agents currently under preclinical evaluation for the GI-ARS has been reported by Shadad and colleagues [86]. These promising radiation preventive/mitigative treatments for GI injury include, but are not limited to the following: 1) Dietary approach apparently serves to promote mucosal healing in experimental rat intestines such as glutamine and arginine enriched diet; 2) Vitamin E appears to reduce radiation-associated oxidative stress (as shown by effects in rat intestines); 3) Captopril has a protective effect on mouse intestine via an angiotensin-converting enzyme (ACE) inhibitory action (i.e., inhibition of pro-inflammatory enzyme angiotensin-1-converting enzyme); 4) Rofecoxib radioprotects rat intestine via a selective inhibition of cyclooxygenases-2 enzyme; 5) Clopidogrel radioprotects rat intestine with vascular sclerosis via inhibition of platelets aggregation; 6) Simvastatin attenuates endothelial cells within the gut of experimental rats; 7) Glucagon-like peptide-2 (GLP-2) increases mucosal mass and exerts trophic and protective effects to the irradiated rat gut; 8) Octreotide modulates the inflammatory effects of over expression of nuclear factor-κB (NF-κB) within the irradiated rat intestine, thus ameliorating inflammation and injury in rat intestine; 9) Prostaglandin E-2 promotes countervailing, anti-apoptosis and proliferation, intestinal epithelium results in an increased survival of intestinal crypts following irradiation; 10) Anti-Transforming growth factors-β (TGF-β) receptor mediated: biological inhibition of extracellular remodeling Reduced intestinal injury and fibrosis compared to IgG treated control mice 11) Toll like receptor 5 agonist derived from Salmonella flagellin mediated activation of intestinal immune response via NF-κB signalling pathway Protective effect to mice intestine.
Anti-ceramide antibody.
Irradiation leads to the release of acid sphingomyelinase in minutes to the outer endothelial plasma membrane where it finds its substrate, sphingomyelin, and generates the pro-apoptotic second messenger, ceramide. Ceramide accumulates a signaling platform on the endothelial cell surface that mediates apoptosis [87,88]. The coupling of micro vessel injury to direct intestinal stem cell (ISC) damage coordinately determines ISC survival from the insult of irradiation. The antagonism of the radiation-induced ceramide on the endothelial cell surface inhibits the formation of ceramide-rich platforms required for endothelial cell death, thereby protecting mice against the lethality of GI-ARS. Anti-ceramide monoclonal antibody binds to radiation-induced ceramide, inhibiting the formation of ceramide-rich signaling platforms, ultimately protecting the cell and tissue from radiation-induced apoptosis. This protective effect appears to enhance the recovery of crypt stem cell clonogens in GI tissue of irradiated animals and protect these animals from GI-ARS [89]. Anti-ceramide antibody has been demonstrated to protect C57BL/6 mice when administered prophylactically via intravenous (iv) route 15 min prior to radiation exposure (15 Gy, 2.12 Gy/min) with a 137Cs source [89]. Anti-ceramide antibody and its single chain variable fragment (scFv) have also been studied using supralethal doses of 60Co γ-radiation in C57BL/6 mice, and have been reported to show remarkable efficacy against GI-ARS as revealed by crypt regeneration and mouse survival in conjunction with BM transplantation [90]. Above studies suggest that anti-ceramide antibody represents a new class of radiation countermeasures that may be effective against radiation-induced GI-ARS. This agent is a promising drug and is expected to be evaluated for its pharmacokinetics and efficacy in NHPs.
2.1.2.1. Countermeasures for radiation-induced emesis: Granisetron (Kytril)
In addition to countermeasures that protect from radiation injury or mitigate its effects, there are agents which can provide support if used appropriately. Kytril is one of those agents which provide support to radiation exposed victims, if used appropriately. Kytril is a very effective, anti-emetic drug used clinically to reduce the side-effects of radiotherapy and chemotherapy via its antagonistic effects on 5-hydroxytryptamine (5-HT3). It received FDA approval in 2001 and it significantly minimizes performance-decrementing effects associated with the prodromal response. It is also well-tolerated and effective when administered either as a prophylactic or therapeutic agent [91]. Its po dose is 2 mg/d and can be administered up to 14 days.
Ondansetron is a carbazole-derived serotonin receptor antagonist with anti-emetic activity. Its half-life is shorter than Kytril, and it is claimed to be less effective in the prevention of nausea and vomiting compared to Kytril.
2.1.3. Neurovascular tissue injury- the sub-syndrome of ARS (NV-ARS)
General description.
Clinical symptoms of the NV-ARS occurs relatively early (i.e., minutes to days) following whole-body or cranial exposures that are generally well above 10 Gy in humans. This syndrome results from contained changes in the nervous system and involves injury to the blood–brain barrier, inflammation of the meninges, impaired capillary circulation, petechial hemorrhages, interstitial edema, acute inflammation, and hypertrophy of perivascular astrocytes [92]. Clinical presentations include severe nausea, vomiting, accompanied by headache, neurologic deficits, loss-of-balance, disorientation, confusion, and seizures. Physical examination reveals papilledema, ataxia, and reduced deep tendon and corneal reflexes [4].
Clinical management.
NV-ARS sub-syndrome is extremely difficult, if not impossible, to effectively manage clinically. High radiation dose-induced NV-ARS (referred to in older literature as ‘central nervous system’ or CNS syndrome) is basically untreatable in the conventional sense; available treatment options are extremely limited and are aimed at combating shock and lack of oxygen, relieving pain and anxiety, and providing sedation to control convulsions in addition to psychological support [93].
Mitigative and therapeutic agents in clinical use.
Currently, there are no truly effective mitigative or therapeutic agents in clinical use for this highly lethal sub-syndrome of ARS. At present, treatments are simply supportive in nature and limited to palliatives (e.g., pain relievers such as opioids), with the aim of trying to make the patient as comfortable as possible.
New preventive/mitigative agents currently under preclinical evaluation.
This general area of pharmacotherapeutic research is extremely limited. However, as a result of animal-based studies of health risk assessments associated with space travel, medical countermeasures are being pursued for CNS- related syndromes using rather simple nutritional approaches (i.e., dietary supplements enriched in antioxidants) appear to limit potential CNS risks associated with heavy-ion exposure. Furthermore, ‘earth bound realm’ and ‘cutting-edge’ pharmacologic approaches have identified new species of rather potent antioxidants that serve to effectively scavenge free radicals stemming from high radiation doses. Free radicals such as the hydroxy radical are extremely reactive and short-lived and can be scavenged by very high concentrations of antioxidants, if they are present at the time of irradiation. One such agent is edaravone, a pyrazolone species (2,4-dihydro-3H-pyrazol-3-one with phenyl and methyl substitutions at positions 2 and 5), that has demonstrated strong antioxidant and radical scavenging capacity. Edaravone is a proven neuroprotective agent, currently in clinical use for the treatment of patients with amyotrophic lateral sclerosis and has been shown to slow down the decline of physical function. Another promising pharmacotherapeutic approach has come through the clinical application of recombinant biomolecules, such as bevacizumab (Avastin®, Genentech), for treatments of brain tissue necrosis following high dose cranial irradiations [94].
2.2. Delayed effect of acute radiation exposure (DEARE)
High dose radiation exposure cause ARS which leads to morbidity and mortality. Surviving ARS carries additional health risks that may have dire consequences. In due course, survivors may experience the DEARE, which manifests as chronic illnesses involving multiple organ systems of the body including the lung, BM, GI tract, heart, kidney and the central nervous system [95]. Development of DEARE takes months to years and when fully expressed, these delayed or late effects of acute radiation exposure result in multi-organ failure and death. In the lung, DEARE exhibits as pneumonitis and fibrosis. A better understanding of the mechanisms mediating DEARE is important for countermeasure development for such indications.
2.2.1. Pulmonary tissue injury- a clinical pathology associated ARS
General description.
Radiation-induced lung injury encompasses lung toxicities elicited by either accidental or unwanted radiation exposures or by intentionally applied therapeutic procedures. These lung injuries manifest either acutely as radiation pneumonitis or chronically as radiation pulmonary fibrosis. Major lung cell types injured by acute irradiation include endothelial cells, alveolar macrophages, and Type II pneumocytes. Furthermore, pneumocytes have a surface protein, surfactant-A, thought to be involved in controlling the transit of immune cells into damaged tissue sites following irradiation [96]. These pathologies are clearly linked temporally (with pneumonitis generally expressed early following irradiation and followed later by fibrotic development), but perhaps causally as well. Although precise mechanisms for such causal linkages and pathways remain ill-defined, they are unquestionably tied to the initial radiation exposure event and the associated attack by free radicals on targeted tissues. They are also related to subsequent, persistent inflammatory response that follows and that serve to dysregulate tissue remodeling and ultimately tissue function [96]. A ‘microenvironmental’ (common soil) hypothesis is commonly evoked in order to explain mechanistically linkages between early and late arising pulmonary pathologies, as well as a variety of other radiation-induced disease entities. Early investigations suggested that these initially induced tissue injuries were simply the products of cell loss in either the parenchymal or vascular compartments; however, they are now seen as the result of a complex, orchestrated interaction between multiple cell types, initiated and perpetuated through inter- and intra-cellular signaling [96].
The lung appears to be moderately radiosensitive due to its susceptibility to acute and chronic inflammation [97]. As indicated above, exposure to high doses of thoracic radiation manifest over time in life-threatening lung pathologies. Nonstochastic-type of lung pathologies, i.e. pneumonitis and fibrosis, tend to develop earlier following thoracic exposures compared with lung cancers that are more prevalent following longer post-exposure time [98,99]. The timeframe for manifestation of various symptoms is variable; inflammatory pneumonitis within 2 – 4 months and fibrosis in 4 – 6 months post-irradiation [100-103]. Pneumonitis is revealed in histopathology by interstitial and airspace edema, macrophage infiltration, and loss of epithelium [97].
Experimental animals, especially small rodents, tend to be more resistant to these irradiation-associated pulmonary toxicities when compared to humans. Several animal models have been developed and refined for evaluating pulmonary effects of radiation exposure [104] and the mouse model is well characterized in terms of pulmonary injury [105-107] though this model’s lung pathology diverges from that of humans with respect to blood supply, lobularity, and thickness of the septa [103]. Other well-defined large animal models such as NHPs, canines, and swine have their strengths and weaknesses. In case of swine, limited data is available for either partial-body or TBI though the lung has a similar physiology to human [12,108-110]. These animal models need to be validated for specific injury to the lungs to understand the mechanisms leading to radiation injury and evaluation of countermeasure for pulmonary injury [111].
Clinical management and treatments.
Treatment of acute pneumonitis is dependent on clinical severity and typically responds completely to corticosteroids. However, identifying patients who may progress to fibrosis is challenging and there are limited treatment options [96,112]. Nevertheless, ‘standard of care’ treatments are based largely on the premise that effective mitigation of early arising pneumonitis ultimately will serve to minimize the severity of pulmonary fibrosis and substantially delay its onset. Therefore, current treatment strategies are directed toward limiting tissue inflammation via suitable intervention with appropriate pharmacologics [96,112].
Mitigative and therapeutic agents in clinical use.
A well-worked clinical research approach in managing radiation pneumonitis has been to limit inflammation, especially by the use of anti-inflammatory agents such as glucocorticosteroids. However, the latter treatments are not without potential adverse side-effects, especially when used to treat pulmonary injuries of severely immunocompromised individuals manifesting early stages of ARS. Consequently, non-steroidal anti-inflammatory drugs (NSAID) such as indomethcin (or Indocin/Indocin SR) or related cyclooxygenase-2 (COX-2) inhibitors such as Celecoxib have been studied [96,112].
Promising new preventive/mitigative agents currently under preclinical evaluation.
Much like the clinical research efforts, preclinical research has largely focused on three general classes of pharmacologics with either defined molecular modes of action or molecular targeting specificities. The overall goal of the research effort is to identify and develop new agents that are both safe and effective in terms of mitigating the extent of acute radiation elicited free radicals and associated inflammatory actions on pulmonary tissues.
The three classes and examples of pharmacologics under evaluation include (but are not limited to): 1) inhibitors/mitigators of free radical production such as amifostine, super oxide dismutase SOD) and Manganese SOD (MnSOD); 2) limiting the extent of cell death (e.g, type II pneumocytes) with activators of the phosphoinositide-3-kinase–protein kinase B/Akt (PI3KPKB)/Akt pathway; and 3) minimizing recruitment of inflammatory cells following acute irradiation via use of NSAID (e.g., the use of COX-2 inhibitors).
These preclinically-tested pharmacologics include not only the standard species of chemically-derived radioprotectors (e.g, amifostine) but also a large array of natural products (e.g., nutraceuticals), and as they all have been demonstrated to significantly reduce the incidence of lung injury following acute irradiation, as they all hold a degree of promise. For example, polydatin is a small natural molecule isolated from Polygonum cuspidatum with strong antioxidative properties and demonstrable capacity to mitigate acute inflammation and late arising lung fibrosis [113]. Polydatin appears to exert the latter mitigative effects by inhibiting TGF-β1-Smad3 signaling pathway and epithelial-mesenchymal transition [113].
Other types of anti-inflammatory agents have been evaluated as well, including several different types of pleotrophic statins (e.g., lovastatin) that have well recognized 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitory activity and a documented capacity to improve functional quality of endothelium [96]. Furthermore, post-irradiation treatments with statins such as lovastatin (whether treated immediately following exposure or substantially delayed) not only mitigated onset/severity of pneumonitis, but also enhanced survivability of experimental mice acutely exposed to high doses of thoracic irradiation [96]. These statin-mediated effects are thought to be mediated in part by the regulation/inhibition of immunocompetent cell transit into injured tissues. Likewise, it has been proposed that previously noted injury-mitigating effects of pentoxifylline and dexamethasone treatments are the result of these drugs to regulate immune cell transit into radiation-damaged tissues. The combination of pentoxifylline and α-tocopherol have been demonstrated to be successful as well [114-116].
Novel agents that selectively target and inhibit overexpression of select cytokines, chemokines and growth factors as a consequence of acute lung injury are being pursued as well. In addition, as stated above, BIO 300 is being developed for DEARE [55].
2.2.2. Hepatic tissue injuries- clinical pathologies with associated acute irradiation
General description.
The liver is a vital organ, essential for digesting food and eliminating toxic substances within the body. Liver disease can have numerous etiologies, including underlying genetics, or by a variety of factors such as viruses, alcohol, and irradiation. Independent of the latter etiologies, the major signs and symptoms of liver disease include: jaundice, abdominal pain/swelling, swelling of the extremities (ankles, legs, etc), dark color of urine, dark/ bloody stool, chronic fatigue, nausea/vomiting/loss of appetite, and of course, clinical ‘read-outs’ of functional blood tests (e.g., aspartate transaminase, alkaline phosphatase, gamma-glutamyltransferase, L-lactate dehydrogenase, plasma proteins (albumin and total protein levels), and bilirubin, a blood waste product). Alanine transaminase (ALT) serves as a good example of these diagnostic measures; ALT assists in converting proteins into energy for the liver cells and when liver is damaged, ALT is released abnormally into the bloodstream. Radiation-induced liver disease is relatively rare and is generally associated as an unintended consequence of high dose radiotherapy. Regardless, significant injuries to the liver can occur following these toxic insults and can have dire health consequences to the individuals [117]. The pathological hallmark of the radiation-associated liver disease in humans is hepatic veno-occlusive disease [118]. Although radiation-associated liver disease has been recognized for many decades, it still remains an unresolved clinical problem [119]. However, newer radiotherapeutic procedures have significantly reduced both incidence and severity of these radiation-elicited toxicities [119].
Clinical management and treatments.
Clinical management depends largely on the continuous monitoring of the patient’s liver functions, along with rigorous monitoring/management of fluids; the latter in order to avoid excessive fluid overload while avoiding too rapid diuresis or pericentesis. Pharmacologic treatment options are limited, but agents such as defibrotide, coagulolytic agents, and methylprednisolone offer some potential and utility. In the most severe liver disease, liver transplantation is a possible option as well [120].
Mitigative and therapeutic agents in clinical use.
Clinically useful pharmacologics in mitigating radiation-associated hepatic injuries are currently lacking [121]. Nevertheless, preclinical research has suggested the potential therapeutic utility of pharmacologic strategies that target several different pathobiologic process(es) that might serve to repair/restore liver function (e.g., targeting select cytokines such as TGF-β or use of regenerative transplantation of stem cells, hepatocytes, and liver progenitor cells) [121].
Fibrosis occurs when there is an imbalance in extracellular matrix deposition and degradation. Excessive extracellular matrix build-up leads to scarring and thickening of the affected tissue. The usual tissue architecture is also affected and it results in organ dysfunction [122]. Exposure to radiation increases the production of TGF-β1 within hours after irradiation and persists for months. Many TGF-β ligands are strong drivers of extracellular matrix deposition and have a natural affinity for the extracellular matrix which results into a pool of pro-fibrotic factors at the site of organ damage. Therefore, TGF-β ligands are appealing targets for anti-fibrosis approach. TGF-β1 plays an important role in the induction of fibrosis in various organs.
Promising new preventive/mitigative agents currently under preclinical evaluation.
Recent preclinical studies have suggested that select types of dietary supplements (e.g., nutraceuticals) might be useful in limiting radiation-associated liver toxicities. Progress has been limited, however, due to lack of suitable animal models that carry the prominent pathological hallmark of human disease, namely hepatic veno-occlusive lesions [118]. Despite this, potentially useful hepatoprotective/mitigative agents have been identified; for example, betaine, a native product of beetroots, hesperidin, a naturally occurring citrus flavanoglycone, and melatonin. All of these natural products have a demonstrated capacity to reduced radiation-induced oxidative stress in experimental animals exposed to relatively high levels of ionizing irradiation [123-125].
2.2.3. Kidney tissue injuries- clinical pathologies associated with acute irradiation
General description.
Radiation nephropathy (kidney disease) has a number of well-founded etiologies, including both intentional clinical use of irradiation and unwanted, non-clinical radiation exposures. For example, radiation nephropathy could (and has) occurred as a consequence of accidental exposures to improperly handled medical radiation sources or from nuclear accidents. In the case of the latter, radiation exposures of the kidneys (local or whole-body) would have to be in the range of 5 to 10 Gy. The more common and likely exposure scenario for such nephrotoxic exposures would be the collateral kidney damage that results from clinical conditioning regimens (in preparing/conditioning patients for marrow transplantation). Nephropathy tends to develop very slowly over periods following acute, high dose radiation exposures and is expressed clinically/diagnostically in terms of proteinuria, hypertension, and an incapacity to concentrate urine [126-128]. Although the details of pathogenesis remain uncertain (and currently under investigation); oxidative injury of the glomeruli seems to be a key player in the nephropathologic process(es), along with other local mediators of tissue injury, e.g., TGF-β1 or renin-angiotensin. Despite the seriousness of such radiation-associated kidney injury, ‘radiation elicited nephropathy’ should no longer be viewed as inevitable, progressive, and untreatable’ [127,128].
Due to the extremely slow developing nature of radiation nephropathy, it is not possible in general to predict those subjects that will develop significant nephropathy as a consequence of radiation exposure. Nevertheless, with sufficient radiation exposure, there seems to be a fairly predictable temporal pattern of pathological progression; i.e., initial injury of the glomeruli injury, followed by scarring and subsequently tubular injury. Oxidative injury to the glomeruli seems to play a fundamental, mechanistic role in the nephropathologic process(es), with subsequent tubulointerstitial scarring resulting from local expression of mediators, e.g., TGF-β1 or renin-angiotensin.
Clinical management and treatments.
Patients with radiation nephropathy are clinically managed based on the same ‘standard of care’ principles used to manage any type of hypertensive kidney disease, regardless of the etiology.
Mitigative and therapeutic agents in clinical use.
Clinical management of radiation nephropathy includes attention to control of blood pressure and the use of ACE inhibitors or angiotensin receptor blockers [129,130].
2.2.4. Cardiovascular tissue injuries - clinical pathologies associated with acute irradiation
General description.
The heart is generally thought of as being relatively radioresistant in the context of radiotherapeutic exposures. However, in a broader context, this organ manifests a variety of pathologies over a fairly wide range of radiation doses (i.e., <5 Gy to >10 Gy), with the higher exposures expressing shorter latent periods and lower exposures having extremely long latencies (e.g., decades following exposures) [131,132].
In terms of the relative risk of cardiac disease incidence as a function of radiation exposure, an estimated ~14% increase in risk per Gy has been reported for long-term atomic bomb survivors with documented whole-body exposures ranging from 0 – 4 Gy [131]. It should be noted that this estimate is considerably higher than the ~3% per Gy value reported for women undergoing radiotherapy for breast cancer [131,133].
The documented acute radiation associated heart diseases encompass no less than four types of pathologies, namely pericarditis, pericardial and diffuse myocardial fibrosis, coronary arterial, and possible valvular disease [131].
Experimental work using a variety of preclinical animal models clearly support these clinical findings of cardiovascular disease in acutely irradiated humans; e.g., rats receiving local, high cardiac doses (>10 Gy) resulted in extremely high rates of heart disease and ultimately cardiac collapse. Exudative pericarditis occurred after four months, with focal myocardial damage secondary to progressive capillary damage. Estimated LD50 values at 1 year post-irradiation were estimated to be between 15 to 20 Gy [134].
Clinical management and treatments.
As the cardiovascular disease complex is not unique or specific to radiation exposure, the basic practices and ‘standards of care’ of cardiac patients apply. Furthermore, and in terms of clinically managing ‘at risk’ patients with acute radiation exposure histories, standard cardiovascular risk factors, e.g., hypertension and hyperchololemia, need to be accounted for and treated accordingly; this is in order to improve future clinical outcomes [131].
Mitigative and therapeutic agents in clinical use.
Acute pericarditis presenting early, within weeks following irradiation can be effectively treated most often with NSAID. By contrast, effectively treating late-arising or persistent pericarditis, especially in combination of recurrent effusions, can be problematic with more radical treatments required (e.g., pericardiocentesis, subtotal pericardiectomy) [135].
Given the suspected causal linkages between the initial radiation-induced tissue inflammation and other ‘down-stream’ cardiovascular pathologies (e.g., pericardial and diffuse myocardial fibrosis), it would seem reasonable and prudent to use anti-inflammatory drugs for both mitigative and therapeutic purposes.
Promising new preventive/mitigative agents currently under preclinical evaluation.
The use of preclinical animal models of radiation-induced cardiovascular studies have yielded several different pharmacologics that show promise in preventing or mitigating radiation-induced heart disease. However, to date, none of the below listed agents have proven to be clinically effective. Some of these agents tested include the following: captopril, amifostine, methylprednisolone, melatonin, and pentoxifylinne in combination with α-tocopherol [136-140].
2.2.5. Reproductive tissue injuries- clinical pathologies associated with acute irradiation
General description.
Radiation-induced infertility is not an uncommon, life-changing consequence of radiotherapy, especially in children [141]. The risk of radiation injury to the hypothalamic-pituitary gonadal axis is related to the treatment volume, total dose, fractionation schedule, and age at treatment. Induced insufficiencies in gonadotropin may delay sexual development, while deficiencies of follicle stimulating hormone and luteinizing hormone secretion limits circulating sex hormone levels that in turn impact fertility [141]. For men treated early on for childhood cancer, there is significant risk of gonadal injury, especially if the radiotherapy fields include the pelvis or the gonads [141]. In brief, sperm production is reduced in a dose-dependent fashion following radiation. The effects of lower doses of radiation (1 – 3 Gy)) on spermatogenesis is reversible but irreversible at doses >3 Gy.
Like the male reproductive system, the female reproductive system is also susceptible to radiation damage, but even more so. The human oocyte has been estimated to have LD50 value of <2 Gy [142]. The functional unit of the ovary is the ‘follicle’ and is comprised of the oocyte and its companion somatic granulosa cells: the latter dividing cells are thought to be the initial target/site of radiation damage and ultimate contributor of follicular death [142]. Irradiation of the ovaries leads to a reduction in the number of ova with the consequence of a dose-dependent earlier onset of the menopause.
Clinical management and treatments.
Accurate placement of pelvic shields during radiotherapeutic procedures remains a primary preventive measure.
Promising new preventive/mitigative agents currently under preclinical evaluation.
One such new ovarian protection strategy, involves the use of sphingosine-1-phosphate, a ceramide antagonist and negative regulator of apoptosis. This agent has been recently evaluated using preclinical animal models of radiation damage and shown to be quite effective in protecting ovarian reserves of irradiated females and, in turn, protection of their reproductive capacity.
It should be pointed out however that the latter observations related to ‘prophylaxis’ and not to ‘mitigative’ or ‘therapy’ per se. Pharmacologic treatments following acute irradiation for ovarian damage would not be relevant if the ovarian reserve had been depleted completely by irradiation. However, if a small fraction of follicles remain viable, there may be a benefit in targeting the ovarian stroma.
As stated previously, radiation-induced fibrosis is a common long-term side effect of radiation damage within tissues and organ systems, including reproductive system. There has been some experimental success in reversing induced fibrosis: treatments with agents such as copper/zinc SOD, MnSOD, or a combination of pentoxifylline and α-tocopherol [114-116], have shown positive results.
2.2.6. Eye injuries- clinical pathologies associated with acute irradiation
General description.
The eye is subject to extremely high acute radiation exposures (e.g., 1.8 to 2.0 Gy per dose fraction up to 40, 50, 60 Gy total dose) under various conditions. The lens of the eye has long been considered a radiosensitive tissue, but recent work has indicated that the radiosensitivity is even greater than previously thought. Several pathologies can and do occur, but are much delayed in time (1 – 3 years) following irradiation. These eye injuries (pathologies) include neuropathy, retinopathy, and severe dry-eye syndromes and all contribute to a marked reduction in visual acuity. The majority of patients who develop severe dry-eye syndrome become severely symptomatic within a relatively short post-exposure period (~1 month), whereas corneal opacification and vascularization often manifest within 9 – 10 months following radiotherapy [143]. Epidemiological evidence suggests that radiation doses much lower than previously thought can produce cataracts and this led the International Commission on Radiological Protection to recommend reducing dose threshold for vision-impairing cataracts and reducing an occupational equivalent dose limit for the lens in 2011, when only a single threshold of 0.5 Gy was recommended. On the basis of epidemiological evidence, it was assumed that progression of opacities into vision impairing cataracts had no dose rate effect. The above recommendations are based on epidemiological support since there are small number of studies providing explicit biological, mechanistic evidence at doses <2 Gy [144,145].
Clinical management and treatments.
In an attempt to control symptoms of severe dry-eye syndrome, treatments such as artificial tears, lubricating ointments, bandage contact lens, and conjunctival flaps have been tried. Topical steroids have also been used, especially for iritis, while corneal ulcers have been treated with topical and/or systemic antibiotics. Retrobulbar alcohol injections may be used in an uninfected painful eye [143].
Mitigative and therapeutic agents in clinical use.
Dietary ‘polyunsaturated fatty acid’ supplementation has been suggested as a valid therapeutic aid [146].
2.2.7. Oral cavity and salivary glands
General description.
Oral and mucosa as well as associated axillary salivary glands are highly susceptible to radiation injury and subsequent pathology. Such toxicities are mostly of concern in cancer patients treated with radiotherapy (specifically head and neck cancer treatment). Sizable numbers of patients each year undergoing radiotherapy for cancers of the head and neck suffer from radiation-induced mucosal lesions of the throat and mouth, attributed largely to salivary gland dysfunction and salivary output. Such radiation injury contributes to a ‘diminished quality of life’ for these individuals [147]. Further, in severe cases, treatment schedules may be interrupted.
Clinical management and treatments.
Clinical management of radiation-induced xerostomia (dry mouth) is based, first and foremost, on employing radiotherapeutic protocols that are designed to protect salivary glands. Beyond the latter, there are several palliative treatments currently in clinical use, including artificial saliva/mouth moisturizers and muscarinic-cholinergic agonists that stimulate salivary secretions. Examples of such pharmacologics include pilocarpine and cevimeline. Both these drugs are fairly effective in improving salivary flow, but both have their own set of adverse side-effects (e.g., nausea, diarrhea, etc).
Pharmacologics have been developed as well; some intended to provide temporary relief of symptoms (as indicated above), while others are aimed at the protection and/or restoration of glandular function. One such pharmacologic is amifostine, clearly effective in mitigating xerostomia, but has the toxic side-effect of inducing nausea in selected patient [148].
Promising new preventive/mitigative agents currently under preclinical evaluation.
Recent preclinical research has focused on the potential therapeutic utility of recombinant growth factors in mitigating salivary gland dysfunction caused by high dose irradiation [147,149,150]. In general, these are endocrine-related recombinant proteins that have the capacity to activate cellular signaling pathways promoting cell survival, DNA repair, and growth, and therefore, have potential restorative powers for radiation-injured glands. For example, post-irradiation treatments with the recombinant insulin growth factor-1 has been shown to restore salivary gland function potentially through normalization of cell proliferation and improved expression of amylase. Other examples of recombinants under study include such agents as ‘palifermin’, a keratinocyte growth factor with well documented epithelial healing capacities, and basic fibroblast growth factor (bFGF), an agent with not only reparative capacity, but also an ‘anti-apoptotic’ effect as well. Relative to the latter biologics, rather novel methods have been developed for delivery of these recombinants to targeted, radiation-injured salivary glands. One method, for example, entails the use of polymer spheres loaded with bFGF for the delayed release of the injury-mitigative recombinant, while another method makes use of adenoviral vectors to transfer a variety of reparative recombinants (e.g., bFGF, vascular endothelial growth factor, etc). Results of a clinical trial for the use of adenoviral mediated gene transfer in treating persons with chronic radiation induced xerostomia has been reported previously [151].
2.3. Chronic radiation and/or low-dose radiation syndromes
General.
Relative to ‘deterministic’ (non-stochastic) types of radiation-induced syndromes, pathological responses that arise in a delayed fashion from either chronic irradiation or from earlier acute exposures of variable intensities are largely comparable to those that arise following acute exposures (as previously described). However, there are several, prominent differences to be noted, not only in terms of incidence and severity, but also the temporal patterns of expression. Relationships between the conditions of exposure (e.g., TBI, partial-body, continuous or discontinuous exposures), the onset, the severity, and overall incidence of specific syndromes within a given exposed population have been extensively investigated in both human subjects and preclinical studies using various animal models [152-154].
In addition to the ‘deterministic’ subtype of induced pathologies, there is still another major, prominent stochastic subtype of radiation elicited disease, namely ‘cancer’ and its many varieties and forms. In contrast to the former subtype and its more predictable nature (for the individual) based on radiological exposure conditions, the latter subtype is more ‘probabilistic’ in nature, with associated risks of disease development based on the exposed population at large (rather than on the exposed individual per se). There are rather distinct temporal patterns and time-frames for select-types of cancer to develop following radiation exposure, regardless of whether the exposure is acute or chronic. In brief, cancers of the hematopoietic system (e.g., leukemias) tend to manifest earlier in time than do the solid-type of cancers (e.g., sarcomas, carcinomas) [155-157].
Clinical management and treatments.
Before application of specific clinical management protocols, one needs to consider that ‘prevention’ is key in limiting the health impact(s) of chronic irradiation, or to a lesser extent, of low-dose exposures. Guiding principles of basic radiation hygiene need to be kept in mind in order to minimize cumulative radiation dose and intensity. These major ‘principles’ are to: i) minimize exposure time, ii) maximize distance from the source, and iii) use appropriate shielding whenever/wherever possible. Again, the bottom line here is ‘prevention’, and it is absolutely essential in limiting any/all ‘late-arising’, adverse health impacts of these types of radiation exposures. However, in the absence of such preventive methods, exposed subjects need to be properly identified and assessed, both radiologically and for health status. Clinical management and treatment procedures would generally follow those previously outlined when attempting to manage and to treat acutely irradiated subjects bearing specific types of injuries. For example, one of the well-recognized late-arising pathological sequelae resulting from high-dose irradiation of the lung, regardless of whether or not irradiation is delivered acutely or chronically, is characterized initially by pneumonitis and followed by a much delayed expression of lung fibrosis. Since the latter ‘deterministic-type’ pulmonary pathologies are clearly linked temporally and quite possibly causally, and are associated with high morbidity and mortality, treatments following high-dose irradiation need to start treatments that mitigate the delayed pulmonary syndrome, specifically pulmonary fibrosis. Two drugs are FDA-approved for idiopathic pulmonary fibrosis: nintedanib (Ofev) and pirfenidone (Esbriet) [110].
Effective clinical management of the ‘stochastic-type’ of late-arising, radiation-induced pathologies (e.g., precancerous lesions) is clearly more problematic (i.e., compared with managing ‘deterministic’-type of injuries/syndromes). One of the prominent effects of radiation exposure on normal tissues is mutagenesis; a fundamental process, often believed to be an underlying ‘driver’ or basis for radiation-induced malignancies. Exposure to high levels of irradiation delivered either acutely or chronically can cause not only acute health effects (as discussed previously), but can also result in long-term health effects such as cancer and cardiovascular disease. Similarly, low doses of radiation, either continuous or intermittent can also lead to malignancies. There are several classes of anti-cancer agents in clinical use. These agents include: alkylating agents, natural products, anti-metabolites, and hormones [158].
Promising preventive/mitigative agents under preclinical evaluation.
Several classes of anti-mutagenic/anti-carcinogenic agents have been, and continue to be, under preclinical investigation. The more prominent of these include the phosphorothioates (e.g., amifostine/WR1065) and the nitroxides (e.g. Tempol) [159-165]. The phosphorothioates are highly effective radioprotectors when used prophylactically, but have significant side-effects when administered at doses that promote survival. However, studies over the last several decades have demonstrated that these agents can be administered following irradiation and can still retain significant anti-mutagenic (and presumably, anti-carcinogenic) effects and can do so at much lower, non-toxic dosing levels [162].
2.4. Cutaneous tissue injuries- clinical pathologies associated with both acute and late/chronic irradiation
General description.
In response to radiation exposures, acute/early as well as late skin reactions occur. These manifestations are somewhat different. Radiation exposure of skin with significantly high doses (e.g., ~20 Gy or higher) results in a distinct clinical manifestation, distinguished by a transitory and faded erythema within a few hours, followed by acute erythema, blistering, and necrosis in sequence. The necrosis generally occurs 10 – 30 days after exposure, but in very severe instances, necrosis may appear within two days [166-168].
Clinical management and treatments.
Recommended treatment strategy is the use of systemic as well as topical anti-inflammatory agents soon after the exposure. Such treatments reduce the need for surgery [167]. The excision of the affected tissue is the latest strategy in order to prevent recurrent necrosis.
Mitigative and therapeutic agents in clinical use.
More current therapy might make use of transplanted autologous keratinocytes combined with allogeneic stem cell use [169,170]. There is increased interest in stromal cell/mesenchymal stem cell use, progenitor cells, and also adipose stromal cells for cell and gene therapy [169-178].
Promising new preventive/mitigative agents currently under preclinical evaluation.
Swine appears to be the optimal model for the study of cutaneous effects of radiation exposure. PrC-210 [179], Fibroblast growth factor-P [180], Pravastatin [181], Plerixafor [182], and curcumin [183,184] have demonstrated efficacy for cutaneous radiation syndrome in various preclinical models.
3. Preventive, mitigative and therapeutic agents for internalized radionuclides
Though limited agents have received FDA approval, a large number of countermeasures are under development as radioprotectors, mitigators, and therapeutics for radiation injuries [2,44,45].
3.1. FDA-approved medicinals for internalized radionuclides
Internal radiological contamination remains a threat to military and civilians because radionuclides may be internalized through ingestion, inhalation, and wound contamination. A nuclear detonation may result in the release of >400 radioactive isotopes and out of these, ∼40 may be potential health hazards because of their long radiological half-lives or their ability to concentrate in critical organ systems. Internalized radionuclides, either accidentally or from a deliberate attack, need treatment without delay. The treatment options for such internalized radionuclides vary, and each treatment decision carries some risk. In most cases, the benefits of treatment outweigh the risks.
The FDA has approved four agents to prevent uptake or treat individuals exposed to internalized radionuclides (table 3). These agents include potassium iodide (KI; ThyroShield), Prussian Blue (ferric hexacyanoferrate), trisodium zinc diethylenetriaminepentaacetate (Zn-DTPA), and trisodium calcium diethylenetriaminepentaacetate (Ca-DTPA) [185]. These are used to block uptake, bind/dilute, or chelate internalized radionuclides. Though these agents are fully approved by the FDA, apart from KI, direct evidence that these agents provide significant clinical benefit to individuals with internalized radionuclides remains limited.
Table 3.
FDA-approved medicinals for internalized radionuclides
| Agent | Mode of action | Dose | Comments | References* |
|---|---|---|---|---|
| ThyroShield (KI) | Blocks uptake of 131I in thyroid gland | Dose vary from 16 mg for infant to 130 mg for the adults over 40 years | Provides limited protection to the thyroid and the time window for administration is narrow (~3 – 4 h) | [186,187] |
| Prussian Blue/Radiogardase | Binds to 137Cs and various forms of thalium | one g (pediatric) – 3 g (adult) po three times per day | Used to reduce body burden by blocking the absorption and uptake of the nuclides in gastrointetinal tract leading to chelation and excretion, not meant for prophylactic use. | [188,189] |
| Ca-DTPA and Zn-DTPA | Chelator for transuranic and rare earth radionuclides | Adults and adolescents - one g once (single dose), children < 12 years - 14 mg/kg once, iv, first dose with Ca-DTPA and then maintenance with Zn-DTPA once daily | Enhances excretion of nuclides, effective against a limited number of internalized radionuclides, most effective when administered within first 24 h, can increase nephrotoxicity of internalized uranium | [190,191] |
3.1.1. Potassium iodide (KI/ThyroShield - blocker)
Radioactive iodine (131I) is internalized through the lungs and digestive tract, and then absorbed by the thyroid gland. Optimally, KI is administered either prior to or soon after exposure to 131I. The thyroid glands of treated individuals absorb this iodine and saturate the gland to prevent the absorption of radioactive 131I. This results in significantly reduced carcinogenic risk to 131I exposed-individuals. ThyroShield is readily available, comparatively non-toxic, and efficacious when administered po.
During the Chernobyl reactor accident, KI was administered to the Polish population and this treatment was considered to be responsible for the greatly reduced occurrence of thyroid cancers in Poland as compared to other countries where KI-treatment was not provided to exposed individuals. The major drawback of KI treatment is that the protection it provides is limited to the thyroid and the time-window for the administration of this agent is relatively narrow (~3 – 4 h). In addition, it is effective only against internal contamination with 131I. KI neither protects against any other radionuclide nor prevents or limits the uptake of 131I into other organs [186]. Since KI is easily available to all individuals, the stockpiling of KI in the strategic national stockpile (SNS) was discontinued briefly, but again stockpiled as a result of the Fukushima Daiichi incidence and pediatric concerns [187].
3.1.2. Prussian Blue (PB – binder)
PB is an insoluble ferric hexacyanoferrate (Fe4[Fe(CN)6]3) approved by the FDA and is known as Radiogardase. PB is a binding agent stockpiled in the SNS for the treatment of internalized 137Cs and thallium [188]. It is used to reduce the body burdens by blocking the adsorption and uptake of the nuclides in the digestive tract followed by specific ionic bonding (chelation) and excretion of the internalized isotopes. PB is well-tolerated when administered at 1 – 3 g po three times per day. If PB treatment is initiated soon after radionuclide contamination, the biological half-life of 137Cs can be significantly reduced (67% reduction). PB efficacy can be improved by the concurrent administration of other blocking agents. A major drawback of PB is its limited ability to reduce body burdens to low levels of nuclides when treatment is initiated late after exposure. PB is not envisioned for prophylactic use and patients receiving PB treatments need to be closely monitored [189].
3.1.3. Zn/Ca DTPA (chelators)
DTPA is available as two salts (Zn and Ca) and both can be used to treat individuals with internalized transuranic radionuclides (americium, californium, curium, neptunium and plutonium) and/or rare earth radionuclides (cerium, lanthanum, promethium, scandium and yttrium) [190]. These chelating agents bind with a metal to form a stable and less toxic complex and enhance excretion of nuclides in vivo. The FDA approved these agents in 2003 for treatment of internal contamination and these agents are available in the SNS.
The major shortcoming of this treatment is its effectiveness against a limited number of internalized radionuclides. DTPA should not be used to counter uranium contamination since it is not effective in removing uranium and can in fact increase the nephrotoxicity of internalized uranium. Following contamination with plutonium and uranium, DTPA can be used only if there is <3 mg of uranium in circulation. If the circulatory level of uranium is higher, DTPA treatments need to be reassessed by the treating physicians. Furthermore, if the level of internalized plutonium is high enough to cause adverse tissue reactions, DTPA should be administered irrespective of the level of uranium [191].
Additional agents, such as ammonium chloride, ammonium hydroxide/chloride/phosphate, calcium carbonate, calcium gluconate, sodium alginate, and sodium bicarbonate are used to treat individuals with internalized radionuclides, though these agents are not FDA approved specifically for internal radionuclide contamination.
4. Poly-pharmacy and repurposing approaches
In recent years, the poly-pharmacy approach has been investigated for various indications using multiple agents. There are several examples of the poly-pharmacy and repurposing approaches in the area of radiation countermeasure development for radiation injury [192-194].
The combination of cytokines/growth factors and ACE inhibitor has been demonstrated to enhance radiomitigation in the murine model [195]. The combination of three hematopoietic growth factors including PEG G-CSF (BBT-015), PEG GM-CSF (BBT-007), and PEG (BBT-059), has also demonstrated to enhance radiomitigation in the murine model [195,196]. The combination of ACE inhibitor, Captopril, EUK-207, and salen-Mn complexes was highly effective in mitigating radiation-induced lung damage in Sprague-Dawley rats, a well-established model for radiation-induced lung damage [197,198].
Based on existing information from other radiation countermeasures, it was a logical approach to test whether amifostine could enhance the radioprotective efficacy of other radiation countermeasures that act through a different pathway, or if the efficacy of amifostine could be improved by another agent. Amifostine has been tried with several growth factors and other agents while under development as a radiation countermeasure [199]. Some of the agents which have been combined with amifostine or its derivatives to improve efficacy are G-CSF, metformin, selenium, vitamin-E, gamma-tocotrienol, prostaglandin E2, β-glucan, and roncho-Vaxom [199]. Similarly, there are reports for the combination of flagellin and IL-1β [200], gamma-tocotrienol and Simvastatin/pentoxifylline [201,202], filgrastim and α-tocopherol succinate [203], and PEGfilgrastim and Romiplostim [73].
Repurposing is another important strategy where drugs already used in the clinic for one indication are repurposed for another indication [192]. The available data of the agent already in clinic can fast-track approval of the radiation countermeasures and can be achieved by label extension.
5. Conclusion
The availability of countermeasures for radiation injuries has become a grave need for US homeland security as well as for the military since the terrorist attacks of 9/11. Only three agents have been approved as radiomitigators for H-ARS. In addition, there are four agents approved as blocker/binder/chelator for internalized radionuclides. Furthermore, there are a few agents which have been approved for limited indications [2,44,45].
Since efficacy evaluation for radiological/nuclear countermeasures is not possible in human volunteers, as it would be unethical to expose humans to lethal doses of radiation for which field trials have not been feasible, radiation countermeasures for ARS are being developed following the FDA Animal Rule [24]. It is important to note that there are bottlenecks for developing such agents following FDA Animal Rule. The availability of suitable experimental animal models is one of the restrictive factors for developing radiation countermeasures. Only two large animal models, NHP and canine, have been well-characterized for radiation injury. There are several limitations for using these animals in research and with time, such limitations are increasing and becoming more and more difficult. In recent past, researchers at some institutions are trying to develop and characterize the minipig model, specifically Göttingen and Sinclair strains, for radiation injury and development of radiation countermeasures. These animal models are at preliminary stages of development and the FDA is not comfortable to consider any animal model other than NHP for approving drugs following the Animal Rule. Though there are significant opportunities to develop radiation countermeasures using animals, there are also challenges due to the absence of multiple well-characterized large animal models acceptable to FDA that satisfy each sub-syndrome of ARS and DEARE.
Radiation countermeasures are usually investigated in murine model using 30 d survival as the primary end-point and in a 60-d survival study in NHP and canine. These time periods have been preferred to display the ability of the countermeasures to offer protection against or mitigation of ARS following whole-body or partial-body irradiation. Delayed, late, and chronic effects of whole-body or partial-body exposures is another area of prime interest that is gaining traction in the field of radiation countermeasure development. Radiation Nuclear Countermeasures Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health has created the facility for such long-term studies using the large animal model.
6. Expert Opinion
There are a large number of safe and efficacious radiation countermeasures under development to be used as radioprotective agents for radiological and nuclear events, specifically ARS. However, none of these agents have received FDA approval as of yet and need all additional investigation. All three FDA-approved radiation countermeasures for ARS (Neupogen, Neulasta and Leukine) are radiomitigators (to be administered after radiation exposure). Furthermore, these agents are approved by the FDA specifically for H-ARS. In brief, no radioprotector for either H-ARS or for GI-ARS has been approved by the FDA [2]. In addition, no radiation countermeasure has been approved for GI-ARS, either as a protector or mitigator. Keeping in mind above facts, there is a need for a prudent approach for developing radioprotectors for ARS so that such agents become available sooner rather than later. In terms of national security, the development of such radioprotective agents is significant. It is important to note that radioprotectors (agents administered prior to radiation exposure) would be used for healthy individuals in anticipation of radiation exposure in near future. This means that such agents would involve more risk compared to radiomitigators which will be administered to victims already exposed to radiation. Therefore, radioprotectors need additional regulatory stringency for FDA approval. Amifostine is the only radioprotective agent classified as a cytoprotectant and it is approved by the FDA for human use for narrow clinical indications associated with radiotherapy/chemotherapy [76,77]. There are several cytokines and growth factors (palifermin, erythropoietin, IL-3, IL-11) which have been approved by the FDA for limited indications (mostly cancer patients undergoing chemotherapy and/or radiotherapy) [44].
The challenges facing the development of countermeasures specifically for ARS are multifaceted. Usually, development and approval of such agents must follow the strenuous drug review process of the FDA. Furthermore, when human efficacy data cannot be made available and the agent needs to be approved following the FDA Animal Rule, the regulatory and scientific hurdles may be much higher than the challenges encountered during the usual drug development pathway for approval where an agent can be evaluated in clinic under phase II and III for efficacy [24]. The FDA Animal Rule is meant to develop drugs to counter lethal situations resulting from accidental or deliberate exposure to chemical, biological, radiological, or nuclear agents where human phase II and phase III clinical studies for testing efficacy are not feasible due to ethical reasons. The FDA is expected to grant approval of such agents to treat (or prevent) a life-threatening illness triggered by a permanently disabling agent, provided animal efficacy studies establish that the agent will offer a clinical benefit in humans [24]. Such countermeasures still follow the existing requirements for corroborating the safety/toxicity in clinical studies.
The majority of the radiation countermeasures being developed utilize the phenotype-based drug discovery (PBDD) approach, however, the target-based drug discovery (TBDD) approach is clearly underutilized. An improved drug development strategy might be a hybrid that is more reliant on TBDD for the early discovery through large-scale screening of promising candidates and use PBDD for secondary screening for further development. This should be followed by tertiary analysis to identify the efficacious countermeasures that target the specific sub-syndromes of ARS. Though limited progress has been made in the development and fielding of safe and effective pharmacological agents (specifically radioprotectors) for selected types of acute radiation-associated injuries, significant efforts have been made.
As stated above, during any radiological/nuclear event, limited number of individuals will be exposed to higher doses of radiation leading to H-ARS or GI-ARS. The majority of people will be exposed to low doses of radiation. Some of these victims will have high local dose (partial-body) exposure. Such exposed individuals will develop delayed, late, and chronic effects of radiation. This area has been ignored in the past and needs attention. Furthermore, stochastic effects occur by chance and may occur without a threshold level of dose. Its probability is proportional to the radiation dose and its severity is independent of the dose. The main stochastic effect of radiation exposure is cancer. There are agents which are being developed for various indications, but additional effort is needed to broaden the scope of drug development so that overall health risks associated with both short-term and long-term injuries in various organ systems can be reduced and effectively managed. Future studies should also address potential differences between men and women, as well as countermeasure evaluation and development for special populations (e.g., obese, pediatric, geriatric).
Article highlights.
There are only three FDA-approved radiation countermeasures for ARS (Neupogen, Neulasta and Leukine) and all are radiomitigators for H-ARS.
Currently, no radioprotector for either H-ARS or for GI-ARS has been approved by the FDA for human use.
There are four agents which have been approved as blocker, binder or chelator (ThyroShield, Radiogardase, Zn-DTPA and Ca-DTPA) by FDA for internalized radionuclides.
There are several radiation countermeasures for various sub-syndromes under development that are considered safe and efficacious, however, they have not yet received FDA approval and need additional studies.
Poly-pharmacy is an important approach which uses suboptimal doses of two or more countermeasures with different mechanisms of action to avoid side effects/toxicity and improve the treatment outcome.
Repurposing is another useful approach where FDA-approved agents for one indication are deployed for another indication and such strategy significantly reduces the cost for storing the countermeasures in strategic national stockpile/vendor managed inventory.
There is need for additional FDA-approved agents for delayed, late, and chronic effects of radiation.
Acknowledgements
The opinions or assertions contained herein are the private views of the authors and are not necessarily those of the Uniformed Services University of the Health Sciences, or the Department of Defense. Mention of specific therapeutic agents does not constitute endorsement by the U.S. Department of Defense, and trade names are used only for the purpose of clarification.
Funding:
The authors gratefully acknowledge the research support from the National Institute of Allergy and Infectious Diseases (AAI12044‐001‐07000, Work plan G) to VK Singh.
Footnotes
Declaration of Interest:
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer Disclosures:
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References
Papers of special note have been highlighted as either of interest (*) or of high interest (**) to readers.
- 1.Benjamin GC, McGeary M, McCutchen SR. Assessing medical preparedness to respond to a terrorist nuclear event: Workshop report. 2009; Washington, D.C.: The National Academies Press; 2009 [PubMed] [Google Scholar]
- 2.Singh VK, Seed TM. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures. Int J Radiat Biol 2017;93:851–69** Recent three part elegant review article covering various radiation countermeasures for ARS.
- 3.Pellmar TC, Rockwell S. Priority list of research areas for radiological nuclear threat countermeasures. Radiat Res 2005;163:115–23 [DOI] [PubMed] [Google Scholar]
- 4.Lopez M, Martin M. Medical management of the acute radiation syndrome. Rep Pract Oncol Radiother 2011;16:138–46 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Seed TM, Singh VK. Radiation effects In: Roy MJ, ed. Physician’s Guide to Terrorist Attack. Totowa, NJ, USA: Humana Press; 2003:339–62 [Google Scholar]
- 6.Hall EJ, Giaccia AJ. Radiobiology for the Radiobiologist. 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2012 [Google Scholar]
- 7.Guskova AK, Baysogolov GD. Radiation sickness in man translation of Russian language book Luchevaya Bolezen Cheloveka. Moscow: Izdatel’stvo Meditsina, 1971 [Google Scholar]
- 8.Baranov AE, Guskova AK, Nadejina NM, et al. Chernobyl experiences: biological indications of exposure to ionizing radiation. Stem Cells 1995;13 Suppl:S69–77 [PubMed] [Google Scholar]
- 9.Goans RE, Holloway EC, Berger ME, et al. Early dose assessment following severe radiation accidents. Health Phys 1997;72:513–8 [DOI] [PubMed] [Google Scholar]
- 10.Gianni AM, Bregni M, Siena S, et al. Rapid and complete hemopoietic reconstitution following combined transplantation of autologous blood and bone marrow cells. A changing role for high dose chemo-radiotherapy? Hematol Oncol 1989;7:139–48 [DOI] [PubMed] [Google Scholar]
- 11.Laterveer L, Zijlmans JM, Liehl E, et al. Accelerated platelet reconstitution following transplantation of bone marrow cells derived from IL-6-treated donor mice. Ann Hematol 1996;73:239–45 [DOI] [PubMed] [Google Scholar]
- 12.Williams JP, Brown SL, Georges GE, et al. Animal models for medical countermeasures to radiation exposure. Radiat Res 2010;173:557–78** This article discusses various animal models for developing medical countermeasures.
- 13.Singh VK, Olabisi AO. Nonhuman primates as models for the discovery and development of radiation countermeasures. Expert Opin Drug Discov 2017;12:695–709** This is an important article providing a wealth of information regarding the use of nonhuman primate models for studying rdiation injury and developing radiation countermeasures for acute radiation syndrome following the FDA Animal Rule.
- 14.Singh VK, Newman VL, Berg AN, et al. Animal models for acute radiation syndrome drug discovery. Expert Opin Drug Discov 2015;10:497–517** This article presents the FDA Animal Rule and discusses animal models of ARS used for evaluating radiation countermeasures.
- 15.U.S. Food and Drug Administration. FDA approves Neupogen for treatment of patients with radiation-induced myelosuppression following a radiological/nuclear incident. 2015. Available at: http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/AboutMCMi/ucm443245.htm [Last accessed July 6, 2016]* G-CSF (Neupogen, filgrastim) was the first agent to be approved by the US FDA to increase survival in patients acutely exposed to doses of radiation eliciting hematopoietic ARS.
- 16.U.S. Food and drug Administration. FDA approves Leukine for acute radiation syndrome. 2018. Available at: https://www.fda.gov/downloads/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/AboutMCMi/UCM603226.pdf [Last accessed April 01, 2018]** US FDA approved Leukine for use as a radiomitigator for hematopoietic acute radiation syndrome based on studies in nonhuman primate model of ARS under FDA Animal Rule. It can be used as late as 48 h after radiation exposure and it is effective with minimal supportive care.
- 17.Molineux G, Kinstler O, Briddell B, et al. A new form of filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans. Exp Hematol 1999;27:1724–34 [DOI] [PubMed] [Google Scholar]
- 18.National Institute of Allergic and Infectious Diseases. Pegfilgrastim approved for treating acute radiation syndrome. 2015. Available at: https://www.niaid.nih.gov/topics/radnuc/Pages/pegfilgrastim.aspx [Last accessed August 18, 2016]
- 19.Moroni M, Ngudiankama BF, Christensen C, et al. The Gottingen minipig is a model of the hematopoietic acute radiation syndrome: G-colony stimulating factor stimulates hematopoiesis and enhances survival from lethal total-body gamma-irradiation. Int J Radiat Oncol Biol Phys 2013;86:986–92 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Farese AM, Cohen MV, Katz BP, et al. Filgrastim improves survival in lethally irradiated nonhuman primates. Radiat Res 2013;179:89–100* This study demonstrates filgrastim’s ability to effectively mitigate the lethality of H-ARS in NHP model; NHPs were provided supportive care in this study.
- 21.Singh VK, Newman VL, Seed TM. Colony-stimulating factors for the treatment of the hematopoietic component of the acute radiation syndrome (H-ARS): A review. Cytokine 2015;71:22–37** This is a comprehensive review of colony stimulating factors, G-CSF, GM-CSF and pegylated G-CSF, and includes the recent developments of these growth factors as radiation countermeasures in various animal models and their potential use for treating nuclear/radiological accident victims.
- 22.Cary LH, Ngudiankama BF, Salber RE, et al. Efficacy of radiation countermeasures depends on radiation quality. Radiat Res 2012;177:663–75* Demonstrate the efficacy of G-CSF aginst mixed field (neutron plus gamma-photon) exposure.
- 23.Farese AM, MacVittie TJ. Filgrastim for the treatment of hematopoietic acute radiation syndrome. Drugs Today (Barc) 2015;51:537–48* This is a comprehensive article about filgrastim.
- 24.U. S. Food and Drug Administration. Product development under the Animal Rule. 2015. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm399217.pdf [Last accessed October 20, 2018]
- 25.Amgen Inc. Neupogen (filgrastim) injection for subcutaneous or intravenous use. 2015. Available at: http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf [Last accessed April 02, 2015]* Prescribing information for the use of Neupogen as a radiation countermeasure for hematopoietic acute radiation syndrome.
- 26.Ding NH, Li JJ, Sun LQ. Molecular mechanisms and treatment of radiation-induced lung fibrosis. Curr Drug Targets 2013;14:1347–56 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Reeves G Overview of use of G-CSF and GM-CSF in the treatment of acute radiation injury. Health Phys 2014;106:699–703 [DOI] [PubMed] [Google Scholar]
- 28.International Atomic Energy Agency. The radiological accident in Istanbul. 2000. Available at: http://www-pub.iaea.org/books/IAEABooks/6071/The-Radiological-Accident-in-Istanbul [Last accessed February 11, 2014]
- 29.Dainiak N, Gent RN, Carr Z, et al. First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation. Disaster Med Public Health Prep 2011;5:202–12 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Molineux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des 2004;10:1235–44 [DOI] [PubMed] [Google Scholar]
- 31.Amgen Inc. Neulasta (pegfilgrastim) injection for subcutaneous use. 2015. Available at: http://pi.amgen.com/united_states/neulasta/neulasta_pi_hcp_english.pdf [Last accessed November 19, 2015]* Prescribing information for the use of Neulasta as a radiation countermeasure for hematopoietic acute radiation syndrome.
- 32.Hankey KG, Farese AM, Blaauw EC, et al. Pegfilgrastim improves survival of lethally irradiated nonhuman primates. Radiat Res 2015;183:643–55* This study demonstrates pegfilgrastim’s ability to effectively mitigate the lethality of H-ARS in the NHP model; NHPs were provided supportive care in this study.
- 33.Chua HL, Plett PA, Sampson CH, et al. Survival efficacy of the PEGylated G-CSFs, Maxy-G34, and Neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors. Health Phys 2014;106:21–38 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Farese AM, Cohen MV, Stead RB, et al. Pegfilgrastim administered in an abbreviated schedule, significantly improved neutrophil recovery after high-dose radiation-induced myelosuppression in rhesus macaques. Radiat Res 2012;178:403–13 [DOI] [PubMed] [Google Scholar]
- 35.Kiang JG, Zhai M, Liao PJ, et al. Pegylated G-CSF inhibits blood cell depletion, increases platelets, blocks splenomegaly, and improves survival after whole-body ionizing irradiation but not after irradiation combined with burn. Oxid Med Cell Longev 2014;2014:481392. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Sanzari JK, Krigsfeld GS, Shuman AL, et al. Effects of a granulocyte colony stimulating factor, Neulasta, in mini pigs exposed to total body proton irradiation. Life Sci Space Res (Amst) 2015;5:13–20 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Sanofi-Aventis U.S. LLC. LEUKINE® (sargramostim) for injection, for subcutaneous or intravenous use. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103362s5240lbl.pdf?utm_campaign=20180329%20MCMi&utm_medium=email&utm_source=Eloqua [Last accessed April 01, 2018]* Prescribing information for the use of Leukine as a radiation countermeasure for hematopoietic acute radiation syndrome.
- 38.Gupta S. FDA advisory committee meeting: Study drug Leukine. 2013. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/medicalimagingdrugsadvisorycommittee/ucm350156.pdf [Last accessed October 2, 2016]
- 39.Singh VK, Seed TM. An update on sargramostim for treatment of acute radiation syndrome. Drugs Today (Barc) 2018;54:679–93* This is a comprehensive article about Leukine.
- 40.Mac Vittie TJ, Monroy RL, Farese AM, et al. Cytokine therapy in canine and primate models of radiation-induced marrow aplasia. Behring Inst Mitt 1991;90:1–13 [PubMed] [Google Scholar]
- 41.Hammond WP, Boone TC, Donahue RE, et al. A comparison of treatment of canine cyclic hematopoiesis with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, interleukin-3, and canine G-CSF. Blood 1990;76:523–32 [PubMed] [Google Scholar]
- 42.Clayton NP, Charpentier EJJ, LaCasse ER, et al. Sargramostim significantly improved the mortality rate at Day 60 in a non-human primate model of hematopoietic acute radiation syndrome with minimal supportive care when administered 48 h after total body irradiation. 42nd Conference of the European Radiation Reasearch Society Amsterdam, Netherlands 2016:190 [Google Scholar]
- 43.Gluzman-Poltorak Z, Vainstein V, Basile LA. Recombinant interleukin-12, but not granulocyte-colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: Evidence for the development of a frontline radiation medical countermeasure. Am J Hematol 2014;89:868–73* G-CSF failed to demonstrate radiomitigation in NHPs in the absence of supportive care.
- 44.Singh VK, Garcia M, Seed TM. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part II. Countermeasures for limited indications, internalized radionuclides, emesis, late effects, and agents demonstrating efficacy in large animals with or without FDA IND status. Int J Radiat Biol 2017;93:870–84 [DOI] [PubMed] [Google Scholar]
- 45.Singh VK, Hanlon BK, Santiago PT, et al. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use. Int J Radiat Biol 2017;93:885–906 [DOI] [PubMed] [Google Scholar]
- 46.Kruk I, Aboul-Enein HY, Michalska T, et al. Scavenging of reactive oxygen species by the plant phenols genistein and oleuropein. Luminescence 2005;20:81–9 [DOI] [PubMed] [Google Scholar]
- 47.Akiyama T, Ishida J, Nakagawa S, et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 1987;262:5592–5 [PubMed] [Google Scholar]
- 48.Valachovicova T, Slivova V, Sliva D. Cellular and physiological effects of soy flavonoids. Mini Rev Med Chem 2004;4:881–7 [DOI] [PubMed] [Google Scholar]
- 49.Wu HJ, Chan WH. Genistein protects methylglyoxal-induced oxidative DNA damage and cell injury in human mononuclear cells. Toxicol In Vitro 2007;21:335–42 [DOI] [PubMed] [Google Scholar]
- 50.Dey P, Barros RP, Warner M, et al. Insight into the mechanisms of action of estrogen receptor beta in the breast, prostate, colon, and CNS. J Mol Endocrinol 2013;51:T61–74 [DOI] [PubMed] [Google Scholar]
- 51.McCarty MF. Isoflavones made simple - genistein’s agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses 2006;66:1093–114 [DOI] [PubMed] [Google Scholar]
- 52.Landauer MR, Srinivasan V, Seed TM. Genistein treatment protects mice from ionizing radiation injury. J Appl Toxicol 2003;23:379–85 [DOI] [PubMed] [Google Scholar]
- 53.Ha CT, Li XH, Fu D, et al. Genistein nanoparticles protect mouse hematopoietic system and prevent proinflammatory factors after gamma irradiation. Radiat Res 2013;180:316–25 [DOI] [PubMed] [Google Scholar]
- 54.Landauer MR, Harvey AJ, Kaytor MD, et al. Mechanism and therapeutic window of a genistein nanosuspension to protect against hematopoietic-acute radiation syndrome. J Radiat Res 2019;60:308–17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Humanetics Pharmaceuticals. BIO 300: Development programs. 2016. Available at: http://humanetics.a03.neon.ittrium.com/development-programs [Last accessed July 5, 2017]
- 56.Cheema AK, Mehta KY, Santiago PT, et al. Pharmacokinetic and metabolomic studies with BIO 300, a nanosuspension of genistein, in a nonhuman primate model. Int J Mol Sci 2019;20:1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Tacyildiz N, Ozyoruk D, Yavuz G, et al. Soy isoflavones ameliorate the adverse effects of chemotherapy in children. Nutr Cancer 2010;62:1001–5 [DOI] [PubMed] [Google Scholar]
- 58.Ahmad IU, Forman JD, Sarkar FH, et al. Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. Nutr Cancer 2010;62:996–1000 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Pluristem Therapeutics Inc. Studies of PLX-R18 in ARS. 2017. Available at: http://www.pluristem.com/acute-radiation-syndrome-ars/ [Last accessed December 28, 2017]
- 60.Pinzur L, Akyuez L, Levdansky L, et al. Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells. J Cachexia Sarcopenia Muscle 2018;9:1079–92 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Gaberman E, Pinzur L, Levdansky L, et al. Mitigation of lethal radiation syndrome in mice by intramuscular injection of 3D cultured adherent human placental stromal cells. PLoS One 2013;8:e66549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Ofir R Prophylactic administration of placenta-derived PLX-R18 stromal cells mitigates H-ARS death and promotes BM and peripheral blood lineage recovery in a murine model Radiation Injury Treatment Network. Washington, DC, USA: 2019 [Google Scholar]
- 63.Pluristem Therapeutics Inc. U. S. FDA clears Pluristem’s IND to treat victims exposed to acute radiation. 2018. Available at: http://www.pluristem.com/wp-content/uploads/2018/04/ARS_IND_final_isa.pdf [Last accessed May 1, 2018]* PLX-R18 received IND status and it can be administered up to 96 h following radiation exposure.
- 64.Pluristem Therapeutics Inc. Pluristem announces promising results from non-human primate pilot study of PLX-R18 in acute radiation syndrome. 2017. Available at: https://www.pluristem.com/wp-content/uploads/2017/05/ARS-Pilot-Results_final.pdf [Last accessed October 23, 2018]
- 65.Nagayama H, Misawa K, Tanaka H, et al. Transient hematopoietic stem cell rescue using umbilical cord blood for a lethally irradiated nuclear accident victim. Bone Marrow Transplant 2002;29:197–204 [DOI] [PubMed] [Google Scholar]
- 66.Mouthon MA, Van der Meeren A, Gaugler MH, et al. Thrombopoietin promotes hematopoietic recovery and survival after high-dose whole body irradiation. Int J Radiat Oncol Biol Phys 1999;43:867–75 [DOI] [PubMed] [Google Scholar]
- 67.Mouthon MA, Van der Meeren A, Vandamme M, et al. Thrombopoietin protects mice from mortality and myelosuppression following high-dose irradiation: importance of time scheduling. Can J Physiol Pharmacol 2002;80:717–21 [DOI] [PubMed] [Google Scholar]
- 68.Parameswaran R, Lunning M, Mantha S, et al. Romiplostim for management of chemotherapy-induced thrombocytopenia. Support Care Cancer 2014;22:1217–22 [DOI] [PubMed] [Google Scholar]
- 69.Jacobson AE, Shah N, Setty BA. Romiplostim for therapy-related thrombocytopenia in pediatric malignancies. Pediatr Blood Cancer 2017;64:e26473. [DOI] [PubMed] [Google Scholar]
- 70.Yamaguchi M, Hirouchi T, Yokoyama K, et al. The thrombopoietin mimetic romiplostim leads to the complete rescue of mice exposed to lethal ionizing radiation. Sci Rep 2018;8:10659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Yamaguchi M, Hirouchi T, Yoshioka H, et al. Diverse functions of the thrombopoietin receptor agonist romiplostim rescue individuals exposed to lethal radiation. Free Radic Biol Med 2019;136:60–75 [DOI] [PubMed] [Google Scholar]
- 72.Bunin DI, Bakke J, Green CE, et al. Romiplostim (Nplate) as an effective radiation countermeasure to improve survival and platelet recovery in mice. Int J Radiat Biol 2019;(in press): [DOI] [PubMed] [Google Scholar]
- 73.Wong K, Chang PY, Fielden M, et al. Pharmacodynamics of romiplostim alone and in combination with pegfilgrastim on acute radiation-induced thrombocytopenia and neutropenia in non-human primates. Int J Radiat Biol 2019;(in press): [DOI] [PubMed] [Google Scholar]
- 74.Wang ES, Lyons RM, Larson RA, et al. A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide. J Hematol Oncol 2012;5:71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells 2009;27:424–30 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Seed TM. Radiation protectants: current status and future prospects. Health Phys 2005;89:531–45* Presents radiation countermeasures status and the strategies for their use.
- 77.Brizel DM. Pharmacologic approaches to radiation protection. J Clin Oncol 2007;25:4084–9 [DOI] [PubMed] [Google Scholar]
- 78.Withers HR, Elkind MM. Dose-survival characteristics of epithelial cells of mouse intestinal mucosa. Radiology 1968;91:998–1000 [DOI] [PubMed] [Google Scholar]
- 79.Ch’ang HJ, Maj JG, Paris F, et al. ATM regulates target switching to escalating doses of radiation in the intestines. Nat Med 2005;11:484–90 [DOI] [PubMed] [Google Scholar]
- 80.Carr KE. Effects of radiation damage on intestinal morphology. Int Rev Cytol 2001;208:1–119 [DOI] [PubMed] [Google Scholar]
- 81.McGough C, Baldwin C, Frost G, et al. Role of nutritional intervention in patients treated with radiotherapy for pelvic malignancy. Br J Cancer 2004;90:2278–87 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.McGough C, Wedlake L, Baldwin C, et al. Clinical trial: normal diet vs. partial replacement with oral E028 formula for the prevention of gastrointestinal toxicity in cancer patients undergoing pelvic radiotherapy. Aliment Pharmacol Ther 2008;27:1132–9 [DOI] [PubMed] [Google Scholar]
- 83.McGough C, Baldwin C, Norman A, et al. Is supplementation with elemental diet feasible in patients undergoing pelvic radiotherapy? Clin Nutr 2006;25:109–16 [DOI] [PubMed] [Google Scholar]
- 84.Simone NL, Menard C, Soule BP, et al. Intrarectal amifostine during external beam radiation therapy for prostate cancer produces significant improvements in Quality of Life measured by EPIC score. Int J Radiat Oncol Biol Phys 2008;70:90–5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Henriksson R, Franzen L, Littbrand B. Effects of sucralfate on acute and late bowel discomfort following radiotherapy of pelvic cancer. J Clin Oncol 1992;10:969–75 [DOI] [PubMed] [Google Scholar]
- 86.Shadad AK, Sullivan FJ, Martin JD, et al. Gastrointestinal radiation injury: prevention and treatment. World J Gastroenterol 2013;19:199–208 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Paris F, Fuks Z, Kang A, et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001;293:293–7 [DOI] [PubMed] [Google Scholar]
- 88.Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene 2003;22:5897–906 [DOI] [PubMed] [Google Scholar]
- 89.Rotolo J, Stancevic B, Zhang J, et al. Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice. J Clin Invest 2012;122:1786–90* This study reports that an anti-ceramide antibody protects against endothelial apoptosis in the small intestinal lamina propria and facilitates recovery of crypt stem cell clonogens, preventing the death of mice caused by GI-ARS after supralethal radiation doses.
- 90.Singh VK, Fuller J, Rotolo J, et al. Anti-ceramide antibody as treatment for the acute radiation gastrointestinal syndrome. 3rd International Conference on the Molecular Medicine of Sphingolipids French Lick Resort, French Lick, Indiana, USA, 2016 [Google Scholar]
- 91.Kehlet RA, Robinson SI, Young RW, et al. Selection of a drug for prevention of radiation-induced naucea and vomiting In: Reeves GI, Jarrett DG, Seed TM, et al., eds. Triage of Irradiated Personnel Armed Forces Radiobiology Research Institute Workshop. Bethesda, MD: Armed Forces Radiobiology Research Institute; 1996:A7–A17 [Google Scholar]
- 92.O’Connor MM, Mayberg MR. Effects of radiation on cerebral vasculature: a review. Neurosurgery 2000;46:138–49; discussion 50–1 [DOI] [PubMed] [Google Scholar]
- 93.Berger ME, Christensen DM, Lowry PC, et al. Medical management of radiation injuries: current approaches. Occup Med (Lond) 2006;56:162–72 [DOI] [PubMed] [Google Scholar]
- 94.Dahl NA, Liu AK, Foreman NK, et al. Bevacizumab in the treatment of radiation injury for children with central nervous system tumors. Childs Nerv Syst 2019;35:2043–46 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.MacVittie TJ. The MCART consortium animal model series: MCART animal model refinement and MCM development: Defining organ dose, organ-specific tissue imaging, model validation and the natural history between the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE). Health Phys 2015;109:335–41 [DOI] [PubMed] [Google Scholar]
- 96.Williams JP, Johnston CJ, Finkelstein JN. Treatment for radiation-induced pulmonary late effects: spoiled for choice or looking in the wrong direction? Curr Drug Targets 2010;11:1386–94 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97.Travis EL. Organizational response of normal tissues to irradiation. Semin Radiat Oncol 2001;11:184–96 [DOI] [PubMed] [Google Scholar]
- 98.Dagle GE, Sanders CL. Radionuclide injury to the lung. Environ Health Perspect 1984;55:129–37 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99.Van Dyk J, Keane TJ, Kan S, et al. Radiation pneumonitis following large single dose irradiation: a re-evaluation based on absolute dose to lung. Int J Radiat Oncol Biol Phys 1981;7:461–7 [DOI] [PubMed] [Google Scholar]
- 100.Marks LB, Yu X, Vujaskovic Z, et al. Radiation-induced lung injury. Semin Radiat Oncol 2003;13:333–45 [DOI] [PubMed] [Google Scholar]
- 101.Sharplin J, Franko AJ. A quantitative histological study of strain-dependent differences in the effects of irradiation on mouse lung during the intermediate and late phases. Radiat Res 1989;119:15–31 [PubMed] [Google Scholar]
- 102.Sharplin J, Franko AJ. A quantitative histological study of strain-dependent differences in the effects of irradiation on mouse lung during the early phase. Radiat Res 1989;119:1–14 [PubMed] [Google Scholar]
- 103.McLaughlin RF Jr., Tyler WS, Canada RO. Subgross pulmonary anatomy of the rabbit, rat, and guinea pig, with additional notes on the human lung. Am Rev Respir Dis 1966;94:380–7 [DOI] [PubMed] [Google Scholar]
- 104.Chen L, Brizel DM, Rabbani ZN, et al. The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats. Int J Radiat Oncol Biol Phys 2004;60:1520–9 [DOI] [PubMed] [Google Scholar]
- 105.Jackson IL, Vujaskovic Z, Down JD. Revisiting strain-related differences in radiation sensitivity of the mouse lung: recognizing and avoiding the confounding effects of pleural effusions. Radiat Res 2010;173:10–20 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Jackson IL, Vujaskovic Z, Down JD. A further comparison of pathologies after thoracic irradiation among different mouse strains: finding the best preclinical model for evaluating therapies directed against radiation-induced lung damage. Radiat Res 2011;175:510–18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Jackson IL, Xu P, Hadley C, et al. A preclinical rodent model of radiation-induced lung injury for medical countermeasure screening in accordance with the FDA animal rule. Health Phys 2012;103:463–73 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Hopewell JW, Rezvani M, Moustafa HF. The pig as a model for the study of radiation effects on the lung. Int J Radiat Biol 2000;76:447–52 [DOI] [PubMed] [Google Scholar]
- 109.Slauson DO, Hahn FF, Benjamin SA, et al. Inflammatory sequences in acute pulmonary radiation injury. Am J Pathol 1976;82:549–72 [PMC free article] [PubMed] [Google Scholar]
- 110.Garofalo M, Bennett A, Farese AM, et al. The delayed pulmonary syndrome following acute high-dose irradiation: a rhesus macaque model. Health Phys 2014;106:56–72 [DOI] [PubMed] [Google Scholar]
- 111.DiCarlo AL, Jackson IL, Shah JR, et al. Development and licensure of medical countermeasures to treat lung damage resulting from a radiological or nuclear incident. Radiat Res 2012;177:717–21 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112.Hanania AN, Mainwaring W, Ghebre YT, et al. Radiation-induced lung injury: Assessment and management. Chest 2019;156:150–62 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Cao K, Lei X, Liu H, et al. Polydatin alleviated radiation-induced lung injury through activation of Sirt3 and inhibition of epithelial-mesenchymal transition. J Cell Mol Med 2017;21:3264–76 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114.Rivero JA, Shamji O, Kolokythas A. Osteoradionecrosis: a review of pathophysiology, prevention and pharmacologic management using pentoxifylline, alpha-tocopherol, and clodronate. Oral Surg Oral Med Oral Pathol Oral Radiol 2017;124:464–71 [DOI] [PubMed] [Google Scholar]
- 115.Patel V, McGurk M. Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy. Br J Oral Maxillofac Surg 2017;55:235–41 [DOI] [PubMed] [Google Scholar]
- 116.Martos-Fernandez M, Saez-Barba M, Lopez-Lopez J, et al. Pentoxifylline, tocopherol, and clodronate for the treatment of mandibular osteoradionecrosis: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 2018;125:431–39 [DOI] [PubMed] [Google Scholar]
- 117.Toesca DAS, Ibragimov B, Koong AJ, et al. Strategies for prediction and mitigation of radiation-induced liver toxicity. J Radiat Res 2018;59:i40–i49 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Kim J, Jung Y. Radiation-induced liver disease: current understanding and future perspectives. Exp Mol Med 2017;49:e359. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119.Munoz-Schuffenegger P, Ng S, Dawson LA. Radiation-induced liver toxicity. Semin Radiat Oncol 2017;27:350–57 [DOI] [PubMed] [Google Scholar]
- 120.Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic veno-occlusive disease). J Clin Exp Hepatol 2014;4:332–46 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121.Guha C, Kavanagh BD. Hepatic radiation toxicity: avoidance and amelioration. Semin Radiat Oncol 2011;21:256–63 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122.de Andrade CBV, Ramos IPR, de Moraes ACN, et al. Radiotherapy-induced skin reactions induce fibrosis mediated by TGF-beta1 cytokine. Dose Response 2017;15:1559325817705019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Shedid SM, Abdel-Magied N, Saada HN. Role of betaine in liver injury induced by the exposure to ionizing radiation. Environ Toxicol 2019;34:123–30 [DOI] [PubMed] [Google Scholar]
- 124.Pradeep K, Park SH, Ko KC. Hesperidin a flavanoglycone protects against gamma-irradiation induced hepatocellular damage and oxidative stress in Sprague-Dawley rats. Eur J Pharmacol 2008;587:273–80 [DOI] [PubMed] [Google Scholar]
- 125.El-Missiry MA, Fayed TA, El-Sawy MR, et al. Ameliorative effect of melatonin against gamma-irradiation-induced oxidative stress and tissue injury. Ecotoxicol Environ Saf 2007;66:278–86 [DOI] [PubMed] [Google Scholar]
- 126.Baradaran-Ghahfarokhi M Radiation-induced kidney injury. J Renal Inj Prev 2012;1:49–50 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Cohen EP, Robbins ME. Radiation nephropathy. Semin Nephrol 2003;23:486–99 [DOI] [PubMed] [Google Scholar]
- 128.Pomeranz HD, Henson JW, Lessell S. Radiation-associated cerebral blindness. Am J Ophthalmol 1998;126:609–11 [DOI] [PubMed] [Google Scholar]
- 129.Brown NJ, Nakamura S, Ma L, et al. Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int 2000;58:1219–27 [DOI] [PubMed] [Google Scholar]
- 130.Moulder JE, Fish BL, Cohen EP. ACE inhibitors and all receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy. Curr Pharm Des 2003;9:737–49 [DOI] [PubMed] [Google Scholar]
- 131.Darby SC, Cutter DJ, Boerma M, et al. Radiation-related heart disease: current knowledge and future prospects. Int J Radiat Oncol Biol Phys 2010;76:656–65 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 132.Taunk NK, Haffty BG, Kostis JB, et al. Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. Front Oncol 2015;5:39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 133.Patel Z, Huff J, Saha J, et al. Evidence Report: Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure Human Research Program Space Radiation Program Element. Houston, TX: National Aeronautics and Space Administration, Lyndon B. Johnson Space Center; 2016 [Google Scholar]
- 134.Lauk S, Kiszel Z, Buschmann J, et al. Radiation-induced heart disease in rats. Int J Radiat Oncol Biol Phys 1985;11:801–8 [DOI] [PubMed] [Google Scholar]
- 135.Clare GC, Troughton RW. Management of constrictive pericarditis in the 21st century. Curr Treat Options Cardiovasc Med 2007;9:436–42 [DOI] [PubMed] [Google Scholar]
- 136.Reeves WC, Cunningham D, Schwiter EJ, et al. Myocardial hydroxyproline reduced by early administration of methylprednisolone or ibuprofen to rabbits with radiation-induced heart disease. Circulation 1982;65:924–7 [DOI] [PubMed] [Google Scholar]
- 137.Yarom R, Harper IS, Wynchank S, et al. Effect of captopril on changes in rats’ hearts induced by long-term irradiation. Radiat Res 1993;133:187–97 [PubMed] [Google Scholar]
- 138.Kruse JJ, Strootman EG, Wondergem J. Effects of amifostine on radiation-induced cardiac damage. Acta Oncol 2003;42:4–9 [DOI] [PubMed] [Google Scholar]
- 139.Boerma M, Roberto KA, Hauer-Jensen M. Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol. Int J Radiat Oncol Biol Phys 2008;72:170–7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 140.Gurses I, Ozeren M, Serin M, et al. Histopathological evaluation of melatonin as a protective agent in heart injury induced by radiation in a rat model. Pathol Res Pract 2014;210:863–71 [DOI] [PubMed] [Google Scholar]
- 141.Hudson MM. Reproductive outcomes for survivors of childhood cancer. Obstet Gynecol 2010;116:1171–83 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142.Duncan FE, Kimler BF, Briley SM. Combating radiation therapy-induced damage to the ovarian environment. Future Oncol 2016;12:1687–90 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 143.Parsons JT, Bova FJ, Mendenhall WM, et al. Response of the normal eye to high dose radiotherapy. Oncology (Williston Park) 1996;10:837–47; discussion 47–8, 51–2 [PubMed] [Google Scholar]
- 144.Ainsbury EA, Barnard S, Bright S, et al. Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research. Mutat Res 2016;770:238–61 [DOI] [PubMed] [Google Scholar]
- 145.Hamada N, Azizova TV, Little MP. An update on effects of ionizing radiation exposure on the eye. Br J Radiol 2019. (in press) [DOI] [PMC free article] [PubMed] [Google Scholar]
- 146.Sacca SC, Cutolo CA, Ferrari D, et al. The eye, oxidative damage and polyunsaturated fatty acids. Nutrients 2018;10:E668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Grundmann O, Mitchell GC, Limesand KH. Sensitivity of salivary glands to radiation: from animal models to therapies. J Dent Res 2009;88:894–903 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 148.Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000;18:3339–45 [DOI] [PubMed] [Google Scholar]
- 149.Limesand KH, Said S, Anderson SM. Suppression of radiation-induced salivary gland dysfunction by IGF-1. PLoS One 2009;4:e4663. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 150.Limesand KH, Barzen KA, Quissell DO, et al. Synergistic suppression of apoptosis in salivary acinar cells by IGF1 and EGF. Cell Death Differ 2003;10:345–55 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.Baum BJ, Zheng C, Cotrim AP, et al. Transfer of the AQP1 cDNA for the correction of radiation-induced salivary hypofunction. Biochim Biophys Acta 2006;1758:1071–7 [DOI] [PubMed] [Google Scholar]
- 152.Fritz TE. The influence of dose, dose rate and radiation quality on the effect of protracted whole body irradiation of beagles In: Fliedner TM, Feinendegen LE, Hopewell JW, eds. Chronic irradiation: Tolerance and failure in complex biological systems. London: The British Institute of Radiology; 2002:103–13 [Google Scholar]
- 153.Seed TM, Blakely WF, Knudson GB, et al. International conference on low-level radiation injury and medical countermeasures. Mil Med 2002;167:1–143 [Google Scholar]
- 154.Seed TM, Fry SA, Neta R, et al. Prevention and treatments: summary statement. Mil Med 2002;167:87–93 [PubMed] [Google Scholar]
- 155.Seed TM, Fritz TE, Tolle DV, et al. Survival patterns and hemopathological responses of dogs under continuous gamma irradiation In: Broerse JJ, MacVittie TJ, eds. Response of Different Species to Total Body Irradiation. Dordrecht, Netherlands: Martinus Niijhoff; 1984:137–59 [Google Scholar]
- 156.Seed TM, Kaspar LV, Fritz TE, et al. Cellular responses in chronic radiation leukemogenesis In: Huberman E, Barr SH, eds. Carcinogenesis. New York: Raven Press; 1985:363–79 [PubMed] [Google Scholar]
- 157.Upton AC. Biological basis for assessing carcinogenic risks of low-level radiation In: Huberman E, Barr SH, eds. The role of chemicals and radiation in the etiology of cancer, Carcinogenesis- A comprehensive survey. New York: Raven Press; 1985:381–401 [PubMed] [Google Scholar]
- 158.Ali R, Mirza Z, Ashraf GM, et al. New anticancer agents: recent developments in tumor therapy. Anticancer Res 2012;32:2999–3005 [PubMed] [Google Scholar]
- 159.Johnstone PA, DeGraff WG, Mitchell JB. Protection from radiation-induced chromosomal aberrations by the nitroxide Tempol. Cancer 1995;75:2323–7 [DOI] [PubMed] [Google Scholar]
- 160.Grdina DJ, Nagy B, Hill CK, et al. The radioprotector WR1065 reduces radiation-induced mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in V79 cells. Carcinogenesis 1985;6:929–31 [DOI] [PubMed] [Google Scholar]
- 161.Grdina DJ, Kataoka Y, Murley JS. Amifostine: mechanisms of action underlying cytoprotection and chemoprevention. Drug Metabol Drug Interact 2000;16:237–79** This review article discusses amifostine unique chemical design and its mechanisms of action.
- 162.Grdina DJ, Murley JS, Kataoka Y, et al. Relationships between cytoprotection and mutation prevention by WR-1065. Mil Med 2002;167:51–3** This study suggests that the mechanisms of action of amifostine and its metabolites to protect against cell death are different from those that protect against mutagenesis and cancer induction.
- 163.Kataoka Y, Perrin J, Hunter N, et al. Antimutagenic effects of amifostine: clinical implications. Semin Oncol 1996;23:53–7 [PubMed] [Google Scholar]
- 164.Diamond AM, Dale P, Murray JL, et al. The inhibition of radiation-induced mutagenesis by the combined effects of selenium and the aminothiol WR-1065. Mutat Res 1996;356:147–54 [DOI] [PubMed] [Google Scholar]
- 165.Seed TM, Tolle DV, Fritz TE. Haematological responses to chronic irradiation: The past Argonne experience and future AFRRI initiatives In: Fliedner TM, Feinendegen LE, Hopewell JW, eds. Chronic irradiation: Tolerance and Failure in Complex Biological Systems Advanced Research Workshop on Protracted, Intermittent or Chronic Irradiation : Biological Effects and Mechanisms of Tolerence (2001 : Ulm, Germany). London: British Institute of Radiology; 2002:94–102 [Google Scholar]
- 166.Peter RU, Gottlober P, Nadeshina N, et al. Radiation lentigo. A distinct cutaneous lesion after accidental radiation exposure. Arch Dermatol 1997;133:209–11 [DOI] [PubMed] [Google Scholar]
- 167.Peter RU, Gottlober P. Management of cutaneous radiation injuries: diagnostic and therapeutic principles of the cutaneous radiation syndrome. Mil Med 2002;167:110–2 [PubMed] [Google Scholar]
- 168.Peter RU, Braun-Falco O, Birioukov A, et al. Chronic cutaneous damage after accidental exposure to ionizing radiation: the Chernobyl experience. J Am Acad Dermatol 1994;30:719–23 [DOI] [PubMed] [Google Scholar]
- 169.Lataillade JJ, Doucet C, Bey E, et al. New approach to radiation burn treatment by dosimetry-guided surgery combined with autologous mesenchymal stem cell therapy. Regen Med 2007;2:785–94 [DOI] [PubMed] [Google Scholar]
- 170.Bey E, Prat M, Duhamel P, et al. Emerging therapy for improving wound repair of severe radiation burns using local bone marrow-derived stem cell administrations. Wound Repair Regen 2010;18:50–8 [DOI] [PubMed] [Google Scholar]
- 171.Semont A, Francois S, Mouiseddine M, et al. Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury. Adv Exp Med Biol 2006;585:19–30 [DOI] [PubMed] [Google Scholar]
- 172.Abdel-Mageed AS, Senagore AJ, Pietryga DW, et al. Intravenous administration of mesenchymal stem cells genetically modified with extracellular superoxide dismutase improves survival in irradiated mice. Blood 2009;113:1201–3 [DOI] [PubMed] [Google Scholar]
- 173.Saha S, Bhanja P, Kabarriti R, et al. Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice. PLoS One 2011;6:e24072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 174.Agay D, Scherthan H, Forcheron F, et al. Multipotent mesenchymal stem cell grafting to treat cutaneous radiation syndrome: development of a new minipig model. Exp Hematol 2010;38:945–56 [DOI] [PubMed] [Google Scholar]
- 175.Forcheron F, Agay D, Scherthan H, et al. Autologous adipocyte derived stem cells favour healing in a minipig model of cutaneous radiation syndrome. PLoS One 2012;7:e31694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 176.Singh VK, Wise SY, Fatanmi OO, et al. Preclinical development of a bridging therapy for radiation casualties: appropriate for high risk personnel. Health Phys 2014;106:689–98 [DOI] [PubMed] [Google Scholar]
- 177.Singh VK, Wise SY, Fatanmi OO, et al. Progenitors mobilized by gamma-tocotrienol as an effective radiation countermeasure. PLoS One 2014;9:e114078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 178.Horton JA, Hudak KE, Chung EJ, et al. Mesenchymal stem cells inhibit cutaneous radiation-induced fibrosis by suppressing chronic inflammation. Stem Cells 2013;31:2231–41 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Peebles DD, Soref CM, Copp RR, et al. ROS-scavenger and radioprotective efficacy of the new PrC-210 aminothiol. Radiat Res 2012;178:57–68 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 180.Zhang K, Tian Y, Yin L, et al. Fibroblast growth factor-peptide improves barrier function and proliferation in human keratinocytes after radiation. Int J Radiat Oncol Biol Phys 2011;81:248–54 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181.Holler V, Buard V, Gaugler MH, et al. Pravastatin limits radiation-induced vascular dysfunction in the skin. J Invest Dermatol 2009;129:1280–91 [DOI] [PubMed] [Google Scholar]
- 182.Kim JH, Kolozsvary A, Jenrow KA, et al. Plerixafor, a CXCR4 antagonist, mitigates skin radiation-induced injury in mice. Radiat Res 2012;178:202–6 [DOI] [PubMed] [Google Scholar]
- 183.Okunieff P, Xu J, Hu D, et al. Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines. Int J Radiat Oncol Biol Phys 2006;65:890–8 [DOI] [PubMed] [Google Scholar]
- 184.Ryan JL, Heckler CE, Ling M, et al. Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res 2013;180:34–43 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 185.Centers for Disease Control and Prevention. Emergency Preparedness and Response. 2016. Available at: http://emergency.cdc.gov/radiation/countermeasures.asp [Last accessed September 1, 2016]
- 186.American Thyroid Association. Nuclear Radiation and the Thyroid. 2013. Available at: http://www.thyroid.org/wp-content/uploads/patients/brochures/NuclearRadiation_brochure.pdf [Last accessed September 1, 2016]
- 187.Whitcomb RC Jr., Ansari AJ, Buzzell JJ, et al. A public health perspective on the U.S. response to the Fukushima radiological emergency. Health Phys 2015;108:357–63 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 188.Hussar DA. New drugs 05, part I. Nursing 2005;35:54–61; quiz 61–3 [DOI] [PubMed] [Google Scholar]
- 189.Yamamoto LG. Risks and management of radiation exposure. Pediatr Emerg Care 2013;29:1016–26; quiz 27–29 [DOI] [PubMed] [Google Scholar]
- 190.The Radiation Emergency Assistance Center/Training Site. The medical aspects of radiation incidents. 2013. Available at: https://orise.orau.gov/files/reacts/medical-aspects-of-radiation-incidents.pdf [Last accessed October 28, 2016]
- 191.Kazzi ZN, Heyl A, Ruprecht J. Calcium and zinc DTPA administration for internal contamination with plutonium-238 and americium-241. Curr Pharm Biotechnol 2012;13:1957–63 [DOI] [PubMed] [Google Scholar]
- 192.DiCarlo AL, Cassatt DR, Dowling WE, et al. Challenges and benefits of repurposing products for use during a radiation public health emergency: Lessons learned from biological threats and other disease treatments. Radiat Res 2018;190:659–76 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 193.Hofer M, Hoferova Z, Depes D, et al. Combining pharmacological countermeasures to attenuate the acute radiation syndrome -A concise review. Molecules 2017;22:834. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 194.Singh VK, Fatanmi OO, Wise SY, et al. The potentiation of the radioprotective efficacy of two medical countermeasures, gamma-tocotrienol and amifostine, by a combination prophylactic modality. Radiat Prot Dosimetry 2016;172:302–10** The prophylactic combination of amifostine and gamma-tocotrienol, which act through different mechanisms, shows promise and should be investigated further using large animal model as a potential countermeasure for ARS.
- 195.Cox G. Improving survival in a mouse H-ARS model using combinations of hematopoietic growth factors and an ACE inhibitor A poly-pharmacy approach to mitigate acute radiation syndrome (ARS). National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA: 2018 [Google Scholar]
- 196.Plett PA, Chua HL, Sampson CH, et al. PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), and IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome. Health Phys 2014;106:7–20 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 197.Mahmood J, Jelveh S, Zaidi A, et al. Targeting the Renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage. Int J Radiat Oncol Biol Phys 2014;89:722–8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 198.Medhora M. Enhanced mitigation of radiation-induced injuries by combining angiotensin-converting enzyme (ACE) inhibitors with other countermeasures A poly-pharmacy approach to mitigate acute radiation syndrome (ARS). National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA: 2018 [Google Scholar]
- 199.Singh VK, Seed TM. The efficacy and safety of amifostine for the acute radiation syndrome. Expert Opin Drug Saf 2019;18:1077–90 [DOI] [PubMed] [Google Scholar]
- 200.Murzina EV, Sofronov GA, Simbirtsev AS, et al. Radioprotective efficiency of recombinant flagellin and interleukin-1 beta with combined administration. Pharmaceutical Chemistry Journal 2019;52:835–38 [Google Scholar]
- 201.Pathak R, Kumar VP, Hauer-Jensen M, et al. Enhanced survival in mice exposed to ionizing radiation by combination of gamma-tocotrienol and Simvastatin. Mil Med 2019;184:644–51 [DOI] [PubMed] [Google Scholar]
- 202.Kulkarni S, Chakraborty K, Kumar KS, et al. Synergistic radioprotection by gamma-tocotrienol and pentoxifylline: role of cAMP signaling. ISRN Radiol 2013;2013:390379. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 203.Gheita HA, El-Sabbagh WA, Abdelsalam RM, et al. Promising role of filgrastim and alpha-tocopherol succinate in amelioration of gastrointestinal acute radiation syndrome (GI-ARS) in mice. Naunyn Schmiedebergs Arch Pharmacol 2019;392:1237–550 [DOI] [PubMed] [Google Scholar]