Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond

Singh, Vijay K.; Seed, Thomas M.

doi:10.1080/09553002.2021.1969054

Cited by 88Effects of Radiation ExposureHematopoietic Stem Cell TransplantationRadiation Therapy and Dosimetry

Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond

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Singh, Vijay K., Seed, Thomas M.·2021·International Journal of Radiation Biology

DOI 10.1080/09553002.2021.1969054

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Abstract

Purpose The intent of this article is to report the status of some of the pharmaceuticals currently in late stage development for possible use for individuals unwantedly and acutely injured as a result of radiological/nuclear exposures. The two major questions we attempt to address here are: (a) What medicinals are currently deemed by regulatory authorities (US FDA) to be safe and effective and are being stockpiled? (b) What additional agents might be needed to make the federal/state/local medicinal repositories more robust and useful in effectively managing contingencies involving radiation overexposures? Conclusions A limited number (precisely four) of medicinals have been deemed safe and effective, and are approved by the US FDA for the 'hematopoietic acute radiation syndrome (H-ARS).' These agents are largely recombinant growth factors (e.g. rhuG-CSF/filgrastim, rhuGM-CSF/sargramostim) that target and stimulate myeloid progenitors within bone marrow. Romiplostim, a small molecular agonist that enhances platelet production via stimulation of bone marrow megakaryocytes, has been recently approved and indicated for H-ARS. It is critical that additional agents for other major sub-syndromes of ARS (gastrointestinal-ARS) be approved. Future success in developing such medicinals will undoubtedly entail some form of a polypharmaceutical strategy, or perhaps novel, bioengineered chimeric agents with multiple, radioprotective/radiomitigative functionalities.

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FDA-approved radiomitigators such as leukocyte growth factors or megakaryocyte-targeting products that treat hematopoietic effects of acute radiation syndrome are non-viable options for space radiation because their mechanism of stimulating cells to divide may propagate late radiation-induced damage and increase overall carcinogenesis risk.
“FDA-approved radiomitigators such as leukocyte growth factors or megakaryocyte-targeting products that treat the hematopoietic effects of ARS are also non-viable options due to their mechanism of stimulating cells to divide, which may lead to the propagation of late radiation-induced damage, increasing the overall risk of carcinogenesis (Singh and Seed, 2021;Singh et al., 2015).”
From The Need for Biological Countermeasures to Mitigate the Risk of Space Radiation-Induced Carcinogenesis, Cardiovascular Disease, and Central Nervous System Deficiencies (2022) · cites this paper as Singh and Seed, 2021

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Medical Countermeasures for Platelet Regeneration after Radiation Exposure
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Impact of Abbreviated Filgrastim Schedule on Survival and Hematopoietic Recovery after Irradiation in Four Mouse Strains with Different Radiosensitivity
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Effect of recombinant canine granulocyte-macrophage colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation
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A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications
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Radioprotective Effects of ON 01210.Na upon Oral Administration
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Medical and policy considerations for nuclear and radiation accidents, incidents and terrorism
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Mitigative Effects of a Combination of Multiple Pharmaceutical Drugs on the Survival of Mice Exposed to Lethal Ionizing Radiation
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Promegapoietin‐1a, an Engineered Chimeric IL‐3 and Mpl‐L Receptor Agonist, Stimulates Hematopoietic Recovery in Conventional and Abbreviated Schedules Following Radiation‐Induced Myelosuppression in Nonhuman Primates
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The Effect of Palifermin on Chemotherapyand Radiation Therapy–Induced Mucositis: A Review of the Current Literature
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Effect of Recombinant Human Granulocyte Colony-Stimulating Factor on Survival in Lethally Irradiated Mice
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Synthesis and radioprotective effects of novel benzyl naphthyl sulfoxide (sulfone) derivatives transformed from Ex-RAD
Tang, L., Peng, T., Wang, G., Wen, X., Sun, Y., Zhang, S., Liu, S., & Wang, L. (2018) · MedChemComm · doi:10.1039/c7md00573c · Cited by 23 · see citing works
Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes
Gasperetti, T., Miller, T., Gao, F., Narayanan, J., Jacobs, E. R., Szabó, A., Cox, G. N., Orschell, C. M., Fish, B. L., & Medhora, M. M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.634477 · Cited by 23 · see citing works
Romiplostim
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Effects of Recombinant Human Interleukin 11 on Thrombocytopenia and Neutropenia in Irradiated Rhesus Monkeys
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Association of Hematological Nadirs and Survival in a Nonhuman Primate Model of Hematopoietic Syndrome of Acute Radiation Syndrome
Gluzman‐Poltorak, Z., Vainstein, V., & Basile, L. A. (2015) · Radiation Research · doi:10.1667/rr13962.1 · Cited by 21 · see citing works
The MCART Consortium Animal Model Series
MacVittie, T. J. (2015) · Health Physics · doi:10.1097/hp.0000000000000318 · Cited by 20 · see citing works
Romiplostim for therapy‐related thrombocytopenia in pediatric malignancies
Jacobson, A. E., Shah, N., & Setty, B. A. (2017) · Pediatric Blood & Cancer · doi:10.1002/pbc.26473 · Cited by 20 · see citing works
Diverse functions of the thrombopoietin receptor agonist romiplostim rescue individuals exposed to lethal radiation
Yamaguchi, M., Hirouchi, T., Yoshioka, H., Watanabe, J., & Kashiwakura, I. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.03.023 · Cited by 19 · see citing works
Post Treatment With an FGF Chimeric Growth Factor Enhances Epithelial Cell Proliferation to Improve Recovery From Radiation-Induced Intestinal Damage
Nakayama, F., Hagiwara, A., Umeda, S., Asada, M., Goto, M., Oki, J., Suzuki, M., Imamura, T., & Akashi, M. (2010) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2010.04.045 · Cited by 18 · see citing works
If the unlikely becomes likely: Medical response to nuclear accidents
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Combining Pharmacological Countermeasures to Attenuate the Acute Radiation Syndrome—A Concise Review
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Single-Dose Administration of Recombinant Human Thrombopoietin Mitigates Total Body Irradiation-Induced Hematopoietic System Injury in Mice and Nonhuman Primates
Xing, S. J., Shen, X., Yang, J., Wang, X., Ou, H., Zhang, X., Xiong, G.-L., Shan, Y., Cong, Y., Luo, Q.-L., et al. (2020) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2020.07.2325 · Cited by 17 · see citing works
Role of thrombocytopenia in radiation-induced mortality and review of therapeutic approaches targeting platelet regeneration after radiation exposure
DiCarlo, A. L., Kaminski, J., Hatchett, R. J., & Maidment, B. W. (2015) · Journal of Radiation Oncology · doi:10.1007/s13566-015-0201-z · Cited by 17 · see citing works
The Clinical Development of Recombinant Human Interleukin 11 (NEUMEGA™ rhIL‐11 Growth Factor)
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First use of myeloid colony-stimulating factors in humans
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Effects of a granulocyte colony stimulating factor, Neulasta, in mini pigs exposed to total body proton irradiation
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Delivery of a mitochondria‐targeted antioxidant from biocompatible, polymeric nanofibrous scaffolds
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Cytokine therapy in canine and primate models of radiation-induced marrow aplasia.
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Toward Development of Interleukin-11 as a Medical Countermeasure for Use in Radiological/Nuclear Emergencies
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Mast cell growth factor (C-Kit Ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3:in vivo hemopoietic effects in irradiated mice compared toin vitro effects
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Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures
Lazarus, H. M., Armitage, J. O., & Gale, R. P. (2021) · Journal of Radiological Protection · doi:10.1088/1361-6498/ac0bff · Cited by 11 · see citing works
Cancer Incidence in C3H Mice Protected from Lethal Total-Body Radiation after Amifostine
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Substituted Piperazines as Novel Potential Radioprotective Agents
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Preliminary Nonclinical Toxicity, Pharmacokinetics, and Pharmacodynamics of ALXN4100TPO, a Thrombopoietin Receptor Agonist, in CD2F1 Mice
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Proteomic changes by radio-mitigative thrombopoietin receptor agonist romiplostim in the blood of mice exposed to lethal total-body irradiation
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Influence of combined treatment with interleukin 1 and erythropoietin or GM-CSF and erythropoietin on the regeneration of hemopoiesis in the dog after total body irradiation--a preliminary report.
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DAMPs and radiation injury
Yamaga, S., Aziz, M., Murao, A., Brenner, M., & Wang, P. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1353990 · Cited by 67 · see citing works
Medical management of acute radiation syndrome
Dainiak, N., & Albanese, J. M. (2022) · Journal of Radiological Protection · doi:10.1088/1361-6498/ac7d18 · Cited by 40 · see citing works
Effects of Gamma-Tocotrienol on Intestinal Injury in a GI-Specific Acute Radiation Syndrome Model in Nonhuman Primate
Garg, S., Garg, T. K., Wise, S. Y., Fatanmi, O. O., Miousse, I. R., Savenka, A. V., Basnakian, A. G., Singh, V. K., & Hauer‐Jensen, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094643 · Cited by 31 · see citing works
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Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821)
Kumar, V. P., Holmes‐Hampton, G. P., Biswas, S., Stone, S., Sharma, N. K., Hritzo, B. A., Guilfoyle, M., Eichenbaum, G. M., Guha, C., & Ghosh, S. P. (2022) · Scientific Reports · doi:10.1038/s41598-022-07426-7 · Cited by 30 · see citing works
Gamma-tocotrienol, a radiation countermeasure, reverses proteomic changes in serum following total-body gamma irradiation in mice
Rosen, E. T., Fatanmi, O. O., Wise, S. Y., Rao, V. A., & Singh, V. K. (2022) · Scientific Reports · doi:10.1038/s41598-022-07266-5 · Cited by 30 · see citing works
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Development of gamma-tocotrienol as a radiation medical countermeasure for the acute radiation syndrome: current status and future perspectives
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Determination of Lethality Curve for Cobalt-60 Gamma-Radiation Source in Rhesus Macaques Using Subject-Based Supportive Care
Singh, V. K., Fatanmi, O. O., Wise, S. Y., Carpenter, A. D., & Olsen, C. H. (2022) · Radiation Research · doi:10.1667/rade-22-00101.1 · Cited by 27 · see citing works
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The Need for Biological Countermeasures to Mitigate the Risk of Space Radiation-Induced Carcinogenesis, Cardiovascular Disease, and Central Nervous System Deficiencies
Sishc, B. J., Zawaski, J., Saha, J., Carnell, L. S., Fabre, K. M., & Elgart, S. R. (2022) · Life Sciences in Space Research · doi:10.1016/j.lssr.2022.06.003 · Cited by 23 · see citing works
Gamma-Tocotrienol Modulates Total-Body Irradiation-Induced Hematopoietic Injury in a Nonhuman Primate Model
Garg, T. K., Garg, S., Miousse, I. R., Wise, S. Y., Carpenter, A. D., Fatanmi, O. O., van Rhee, F., Singh, V. K., & Hauer‐Jensen, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232416170 · Cited by 22 · see citing works
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Analysis of the Proteomic Profile in Serum of Irradiated Nonhuman Primates Treated with Ex-Rad, a Radiation Medical Countermeasure
Carpenter, A. D., Li, Y., Janocha, B. L., Wise, S. Y., Fatanmi, O. O., Maniar, M. L., Cheema, A. K., & Singh, V. K. (2023) · Journal of Proteome Research · doi:10.1021/acs.jproteome.2c00458 · Cited by 22 · see citing works
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Model for Evaluating Antimicrobial Therapy To Prevent Life-Threatening Bacterial Infections following Exposure to a Medically Significant Radiation Dose
Phipps, A. J., Bergmann, J. N., Albrecht, M. T., Singh, V. K., & Homer, M. J. (2022) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00546-22 · Cited by 20 · see citing works
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Pharmacokinetic and metabolomic studies with a BIO 300 Oral Powder formulation in nonhuman primates
Li, Y., Girgis, M. J., Jayatilake, M. M., Serebrenik, A. A., Cheema, A. K., Kaytor, M. D., & Singh, V. K. (2022) · Scientific Reports · doi:10.1038/s41598-022-17807-7 · Cited by 20 · see citing works
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Effects of Gamma-Tocotrienol on Partial-Body Irradiation-Induced Intestinal Injury in a Nonhuman Primate Model
Garg, S., Garg, T. K., Miousse, I. R., Wise, S. Y., Fatanmi, O. O., Savenka, A. V., Basnakian, A. G., Singh, V. K., & Hauer‐Jensen, M. (2022) · Antioxidants · doi:10.3390/antiox11101895 · Cited by 20 · see citing works
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Radiosensitivity of rhesus nonhuman primates: consideration of sex, supportive care, body weight, and age at time of exposure
Singh, V. K., Carpenter, A. D., Janocha, B. L., Petrus, S. A., Fatanmi, O. O., Wise, S. Y., & Seed, T. M. (2023) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2023.2205123 · Cited by 19 · see citing works
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Genistin: A Novel Estrogen Analogue Targeting ERβ to Alleviate Thrombocytopenia
Tang, X., Liao, R., Zhou, L. H., Yi, T., Ran, M., Luo, J., Huang, F., Wu, A., Mei, Q., Wang, L., et al. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.90483 · Cited by 19 · see citing works
The Radioprotectant, BIO 300, Protects the Lungs from Total-Body Irradiation Injury in C57L/J Mice
Singh, V. K., Serebrenik, A. A., Fatanmi, O. O., Wise, S. Y., Carpenter, A. D., Janocha, B. L., & Kaytor, M. D. (2023) · Radiation Research · doi:10.1667/rade-22-00142.1 · Cited by 18 · see citing works
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Development of radiation countermeasure agents for acute radiation syndromes
Guan, B., Li, D., & Meng, A. (2023) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12339 · Cited by 18 · see citing works
Protein biomarkers for radiation injury and testing of medical countermeasure efficacy: promises, pitfalls, and future directions
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MIIST305 mitigates gastrointestinal acute radiation syndrome injury and ameliorates radiation-induced gut microbiome dysbiosis
Mitra, D., Armijo, G. K., Ober, E., Baker, S., Turner, H. C., & Broustas, C. G. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2458189 · Cited by 17 · see citing works
Raffinose-metabolizing bacteria impair radiation-associated hematopoietic recovery via the bile acid/FXR/NF-κB signaling pathway
Jiao, Y., Ren, J., Xie, S., Yuan, N., Shen, J., Yin, H., Wang, J., Guo, H., Cao, J., Wang, X., et al. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2488105 · Cited by 16 · see citing works
Metabolomic Profiles in Tissues of Nonhuman Primates Exposed to Either Total- or Partial-Body Radiation
Carpenter, A. D., Li, Y., Fatanmi, O. O., Wise, S. Y., Petrus, S. A., Janocha, B. L., Cheema, A. K., & Singh, V. K. (2024) · Radiation Research · doi:10.1667/rade-23-00091.1 · Cited by 16 · see citing works
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A Novel Antithrombocytopenia Agent, Rhizoma cibotii, Promotes Megakaryopoiesis and Thrombopoiesis through the PI3K/AKT, MEK/ERK, and JAK2/STAT3 Signaling Pathways
Chen, W., Zhu, L., Wang, L., Zeng, J., Wen, M., Xu, X., Zou, L., Huang, F., Huang, Q., Qin, D., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214060 · Cited by 13 · see citing works
Transcriptome profile changes in the jejunum of nonhuman primates exposed to supralethal dose of total- or partial-body radiation
Vellichirammal, N. N., Sethi, S., Avuthu, N., Wise, S. Y., Carpenter, A. D., Fatanmi, O. O., Guda, C., & Singh, V. K. (2023) · BMC Genomics · doi:10.1186/s12864-023-09385-3 · Cited by 12 · see citing works
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Pharmacokinetic and Metabolomic Studies with a Promising Radiation Countermeasure, BBT-059 (PEGylated interleukin-11), in Rhesus Nonhuman Primates
Carpenter, A. D., Li, Y., Wise, S. Y., Fatanmi, O. O., Petrus, S. A., Fam, C. M., Carlson, S. J., Cox, G. N., Cheema, A. K., & Singh, V. K. (2024) · Radiation Research · doi:10.1667/rade-23-00194.1 · Cited by 11 · see citing works
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BIO 300: A Prophylactic Radiation Countermeasure for Acute Radiation Syndrome
Singh, V. K., Serebrenik, A. A., Wise, S. Y., Petrus, S. A., Fatanmi, O. O., & Kaytor, M. D. (2024) · Military Medicine · doi:10.1093/milmed/usae156 · Cited by 11 · see citing works
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Pre-Administration of PLX-R18 Cells Protects Mice from Radiation-Induced Hematopoietic Failure and Lethality
Kumar, V. P., Biswas, S., Holmes‐Hampton, G. P., Sheleg, M., Stone, S., Legesse, B., Ofir, R., & Ghosh, S. P. (2022) · Genes · doi:10.3390/genes13101756 · Cited by 11 · see citing works
Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation
Garg, T. K., Garg, S., Miousse, I. R., Wise, S. Y., Carpenter, A. D., Fatanmi, O. O., van Rhee, F., Singh, V. K., & Hauer‐Jensen, M. (2023) · Radiation Research · doi:10.1667/rade-23-00075.2 · Cited by 11 · see citing works
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Oxymatrine, a novel TLR2 agonist, promotes megakaryopoiesis and thrombopoiesis through the STING/NF-κB pathway
Ni, C., Zhou, L., Yang, S., Ran, M., Luo, J., Cheng, K., Huang, F., Tang, X., Xie, X., Qin, D., et al. (2024) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2024.101054 · Cited by 9 · see citing works
Radiation Medical Countermeasures and Use of EPR Biodosimetry to Facilitate Effectiveness of Applied Clinical Procedures
Singh, V. K., Swartz, H. M., & Seed, T. M. (2021) · Applied Magnetic Resonance · doi:10.1007/s00723-021-01444-w · Cited by 9 · see citing works
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Histopathological studies of nonhuman primates exposed to supralethal doses of total- or partial-body radiation: influence of a medical countermeasure, gamma-tocotrienol
Singh, V. K., Wise, S. Y., Fatanmi, O. O., Petrus, S. A., Carpenter, A. D., Lee, S.-H., Hauer‐Jensen, M., & Seed, T. M. (2024) · Scientific Reports · doi:10.1038/s41598-024-56135-w · Cited by 8 · see citing works
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Development of Nanocarrier‐Based Oral Pegfilgrastim Formulations for Mitigating Hematopoietic Acute Radiation Syndrome
Zhu, Y., Tavakol, D. N., Wang, H., He, S., Ponnaiya, B., Zhu, Z., Xiao, Y., Yoshinaga, N., Wu, X., Wu, X., et al. (2025) · Advanced Functional Materials · doi:10.1002/adfm.202421462 · Cited by 8 · see citing works
Iron Deposition in the Bone Marrow and Spleen of Nonhuman Primates with Acute Radiation Syndrome
Day, R. M., Rittase, W. B., Slaven, J. E., Lee, S.-H., Brehm, G. V., Bradfield, D. T., Muir, J. M., Wise, S. Y., Fatanmi, O. O., & Singh, V. K. (2023) · Radiation Research · doi:10.1667/rade-23-00107.1 · Cited by 7 · see citing works
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The potential value of 5-androstenediol in countering acute radiation syndrome
Singh, V. K., & Seed, T. M. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103856 · Cited by 7 · see citing works
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Astragaloside IV accelerates hematopoietic reconstruction by improving the AMPK/PGC1α-mediated mitochondrial function in hematopoietic stem cells
Zhang, L., Xu, W., Zeng, Y., Wang, L., Luo, J., Zhou, X., Mei, Q., Qin, D., Wu, A., Wu, J., et al. (2025) · Chinese Medicine · doi:10.1186/s13020-025-01092-3 · Cited by 6 · see citing works
Radiation Injuries: Acute Radiation Syndrome in Children
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Authors: Singh, V. K., & Seed, T. M.
Affiliations: Uniformed Services University of the Health Sciences (US)
Tech Micro Services, Bethesda, MD, USA
Corresponding author: Singh, Vijay K.
ORCID: Singh, Vijay K.
Venue: International Journal of Radiation Biology
Publisher: Informa UK Limited
Published: 2021-08-31
Volume: 97
Issue: 11
Pages: 1526-1547
ISSN: 0955-3002 (ISSN-L)
1362-3095
DOI: 10.1080/09553002.2021.1969054
OpenAlex: W3194663062
Cited by: 88
References: 118
Citations by year: 2026: 14 · 2025: 22 · 2024: 15 · 2023: 21 · 2022: 14 · 2021: 1 · 2018: 1
FWCI: 6.77
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: public-domain
creativecommons.org/publicdomain/mark/1.0/ (vor)
Locations: International Journal of Radiation Biology (publishedVersion, public-domain)
PubMed (publishedVersion)
Funders: Armed Forces Radiobiology Research Institute/Uniformed Services University of the Health Sciences
Topics: Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
Keywords: hematopoietic acute radiation syndrome, radiation countermeasures, radiation protection, recombinant growth factors, granulocyte colony-stimulating factor, GM-CSF, romiplostim, drug stockpiling, FDA-approved drugs
MeSH terms: Filgrastim, Humans, Radiation Protection, United States, United States Food and Drug Administration, Cytokines, Acute Radiation Syndrome

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Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond

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