Table 4.

Promising radiation countermeasures in the early stages of development.

Countermeasures	Mode of action	Efficacy in animal model of ARS	Remarks	Ref.
ALXN4100TPO	Activates thrombopoietin receptor, stimulates platelet production	DRF = 1.32, 24 h prior to irradiation; DRF = 1.1, 12 h post-irradiation in CD2F1 mice	Not effective against mixed field; exposure	[74,119,119]
Palifermin	Stimulates epithelial cell proliferation, differentiation and upregulation of cytoprotective mechanisms	Significantly promoted the recovery of mucosa from radiation-induced injury demonstrated by mucosal histology, villus height, crypt depth and crypt cell proliferation	Reduce incidence, duration and severity of oral mucositis in patients receiving chemoradiotherapy	[120,121]
Superoxide dismutase (SOD)	Eliminates reactive oxygen intermediates, prevents radiation-induced apoptosis via mitochondrial membrane stabilization	MnSOD over-expression by transgene conferred protection against irradiation induced lung injury	Novel radioprotective antioxidant gene therapy to prevent and reduce radiation injury	[123–126]
Captopril	ACE protease inhibitor, increases prostaglandin E2	Accelerates recovery of erythrocytes, reticulocytes, leukocytes and platelets in mice	Mechanism of action has not been well established	[129,140]
3,3’-Diindolylmethane	Induces ATM-dependent, DDR-like response, enhances radiation-induced ATM signaling and NF-κB activation	Multi-dose schedule protected rodents against lethal doses of TBI up to 13 Gy, when initiated before or after irradiation, DRF = 1.6	Promising radioprotector and radiomitigator against high dose of radiation	[146]
Oltipraz	Induces electrophile detoxication enzymes, enhances expression of microsomal epoxide hydrolase and glutathione S-transferase genes	When administered orally 30 min prior to 8 Gy TBI, increased mouse survival	Oral efficacy needs to be investigated	[147,148]
Phosphoinisitide-3 kinase inhibitor (LY294002)	Regulates cellular signaling networks linked to survival, growth, proliferation, metabolism and differentiation of cells	Single administration after a lethal dose of γ-irradiation enhanced mouse survival, decreased DNA damage	Pharmacological approaches aimed at radiomitigation should be pursued	[149]
Fibroblast growth factor peptide	Enhances barrier functions and tight-junction protein production, improves cell proliferation, enhances DNA homologous repair and accelerates radiation-induced wound healing	Single dose of FGF-P (≤ 2 mg/kg) 24 h after TBI increased C57Bl/6 mouse survival	Also holds promise for thermal burns, ischemic wound healing, tissue engineering and stem-cell regeneration	[152,153]
Rspo1	Induces Wnt-β-catenin pathway and promotes intestinal stem cell regeneration	Improved survival of mice exposed to TBI and protects against GI syndrome	Rspo1 acts as a mitogenic factor for intestinal stem cells	[154]
GRI977143	Activates LPA2 receptors, ERK1/2 pro-survival pathway reducing BAX translocation, attenuates the activation of initiator and effector caspases, reduces DNA fragmentation and inhibits PARP-1 cleavage	Effective in rescuing mice from lethal irradiation when administered 24 h after exposure	Effectively reduces BAX translocation to the mitochondrion	[155]
Somatostatin analog (SOM230)	Preserves intestinal barrier function by decreased secretion of pancreatic enzymes	Effective radioprotector and radiomitigator	Effective with administration times in excess of 48 h post-irradiation	[156,157]
Insulin-like growth factor 1 (IGF-1)	Restores salivary gland function through normalization of cell proliferation and improved amylase expression	Accelerates hematopoietic recovery	Clinically safe	[159]
Anticeramide antibody	Protects endothelial apoptosis in the small intestinal lamina propria and facilitates recovery of crypt stem cells	Prevents death of mice from GI syndrome after high radiation doses	Promising agent for GI syndrome	[160]
Phenylbutyrate	Inhibits histone deacetylase, cell proliferation, cell cycle arrest, DNA methylation, activates peroxisome proliferator-activated receptors, increases gap junction communication	DRF of 1.31 in DBA/2 mouse model in protector schedule, also functions as a mitigator	Attenuates DNA damage and inhibit radiation-induced apoptosis	[161]
17-DMAG	Inhibits nitric oxide synthase, caspase-3 cascade and p53	A single oral dose before irradiation increased survival of CD2F1 mice	Not effective as a radiomitigator	[162]

17-DMAG: 17-Dimethylamino-ethylamino-17-demethoxygeldanamycin; ARS: Acute radiation syndrome; DDR: DNA damage response; DRF: Dose reduction factor; GI: Gastrointestinal; Rspo1: R-spondin1; TBI: Total-body irradiation.