Development of gamma-tocotrienol as a radiation medical countermeasure for the acute radiation syndrome: current status and future perspectives

References

• Andersson KG, Mikkelsen T, Astrup P, et al. Estimation of health hazards resulting from a radiological terrorist attack in a city. Radiat Prot Dosimetry. 2008;131(3):297–307.
   PubMed Web of Science ®Google Scholar
• Gale RP. Medical and policy considerations for nuclear and radiation accidents, incidents and terrorism. Curr Opin Hematol. 2017;24:496–501.
   PubMed Web of Science ®Google Scholar
• Gale RP, Armitage JO. Are we prepared for nuclear terrorism? N Engl J Med. 2018;378:1246–1254.
   PubMed Web of Science ®Google Scholar
• Hall EJ, Giaccia AJ. Radiobiology for the Radiobiologist. 7th ed. Philadelphia PA: Lippincott Williams and Wilkins; 2012.
   Google Scholar
• 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;93:851–869.
   PubMed Web of Science ®Google Scholar
• McCann DGC. Radiation poisoning: current concepts in the acute radiation syndrome. Am J Clin Med. 2006;3:13–21.
   Google Scholar
• 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;93:870–884.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Singh VK, Newman VL, Romaine PL, et al. Radiation countermeasure agents: an update (2011-2014). Expert Opin Ther Pat. 2014;24:1229–1255.
   PubMed Web of Science ®Google Scholar
• Stone HB, Moulder JE, Coleman CN, et al. Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries report of an nci workshop, december 3–4, 2003. Radiat Res. 2004;162(6):711–728.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM. Radiation countermeasures for hematopoietic acute radiation syndrome: growth factors, cytokines and beyond. Int J Radiat Biol. 2021;97:1526–1547.
   PubMed Web of Science ®Google Scholar
• Farese AM, MacVittie TJ. Filgrastim for the treatment of hematopoietic acute radiation syndrome. Drugs Today (Barc). 2015;51:537–548.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM. An update on sargramostim for treatment of acute radiation syndrome. Drugs Today (Barc). 2018;54:679–693.
   PubMed Web of Science ®Google Scholar
• Wong K, Bunin DI, Bujold K, et al. Romiplostim (Nplate) alone and in combination with pegfilgrastim (Neulasta) increased survival and reduces incidence, duration, and severity of thrombocytopenia post-iradiation in non-human primates. 66th Annual Conference of Radiation Research Society, Virtual; 2020. [Last accessed 2020 Oct20]. Available at: https://www.radres.org/events/EventDetails.aspx?id=1336280
   Google Scholar
• Hankey KG, Farese AM, Blaauw EC, et al. Pegfilgrastim improves survival of lethally irradiated nonhuman primates. Radiat Res. 2015;183:643–655.
   PubMed Web of Science ®Google Scholar
• Clayton NP, Khan-Malek RC, Dangler CA, et al. Sargramostim (rhu GM-CSF) improves survival of non-human primates with severe bone marrow suppression after acute, high-dose, whole-body irradiation. Radiat Res. 2021;195:191–199.
   PubMed Web of Science ®Google Scholar
• Zhong Y, Pouliot M, Downey AM, et al. Efficacy of delayed administration of sargramostim up to 120 hours post exposure in a nonhuman primate total body radiation model. Int J Radiat Biol. 2021;97:S100–S16.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM. An update on romiplostim for treatment of acute radiation syndrome. Drugs Today (Barc). 2022;58:133–145.
   PubMed Web of Science ®Google Scholar
• Farese AM, Cohen MV, Katz BP, et al. Filgrastim improves survival in lethally irradiated nonhuman primates. Radiat Res. 2013;179:89–100.
   PubMed Web of Science ®Google Scholar
• Lazarus HM, McManus J, Gale RP. Sargramostim in acute radiation syndrome. Expert Opin Biol Ther. 2022;22:1345–1352.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM. Entolimod as a radiation countermeasure for acute radiation syndrome. Drug Discov Today. 2021;26:17–30.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM. BIO 300: a promising radiation countermeasure under advanced development for acute radiation syndrome and the delayed effects of acute radiation exposure. Expert Opin Investig Drugs. 2020;29:429–441.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM. Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems. Expert Opin Pharmacother. 2020;21:317–337.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM. Repurposing pharmaceuticals previously approved by regulatory agencies to medically counter injuries arising either early or late following radiation exposure. Front Pharmacol. 2021;12:624844.
   PubMed Web of Science ®Google Scholar
• U.S. Food and Drug Administration. Guidance document: product development under the animal rule. 2015. [Last accessed 2022 Oct 20]. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm399217.pdf
   Google Scholar
• Williams GM, Kobets T, Iatropoulos MJ, et al. GRAS determination scientific procedures and possible alternatives. Regul Toxicol Pharmacol. 2016;79(Suppl 2):S105–11.
   PubMedGoogle Scholar
• Singh VK, Beattie LA, Seed TM. Vitamin E: tocopherols and tocotrienols as potential radiation countermeasures. J Radiat Res. 2013;54:973–988.
   PubMed Web of Science ®Google Scholar
• Papas A. The vitamin factor. New York NY: Harper Perennial, Harper-Collins Publishers Inc; 1999.
   Google Scholar
• Nesaretnam K. Multitargeted therapy of cancer by tocotrienols. Cancer Lett. 2008;269:388–395.
   PubMed Web of Science ®Google Scholar
• Traber MG, Packer L. Vitamin E: beyond antioxidant function. Am J Clin Nutr. 1995;62:1501S–09S.
   PubMed Web of Science ®Google Scholar
• Traber MG, Sies H. Vitamin E in humans: demand and delivery. Annu Rev Nutr. 1996;16:321–347.
   PubMed Web of Science ®Google Scholar
• Papas A. Vitamin E: tocopherols and Tocotrienols. In: Papas AM, editor. Antioxidant status, diet, nutrition, and health. Boca Raton: CRC Press; 1999. p. 189–210.
   Google Scholar
• Palozza P, Simone R, Picci N, et al. Design, synthesis, and antioxidant potency of novel alpha-tocopherol analogues in isolated membranes and intact cells. Free Radic Biol Med. 2008;44:1452–1464.
   PubMed Web of Science ®Google Scholar
• Palozza P, Verdecchia S, Avanzi L, et al. Comparative antioxidant activity of tocotrienols and the novel chromanyl-polyisoprenyl molecule FeAox-6 in isolated membranes and intact cells. Mol Cell Biochem. 2006;287:21–32.
   PubMed Web of Science ®Google Scholar
• Singh VK, Hauer-Jensen M. Gamma-tocotrienol as a promising countermeasure for acute radiation syndrome: current status. Int J Mol Sci. 2016;17:e663.
   PubMed Web of Science ®Google Scholar
• Singh VK, Kulkarni S, Fatanmi OO, et al. Radioprotective efficacy of gamma-tocotrienol in nonhuman primates. Radiat Res. 2016;185:285–298.
   PubMed Web of Science ®Google Scholar
• Garg S, Garg TK, Miousse IR, et al. Effects of gamma-tocotrienol on partial-body irradiation-induced intestinal injury in a nonhuman primate model. Antioxidants. 2022; Vol. 11. p.1895.
   Google Scholar
• Garg TK, Garg S, Miousse IR, et al. Gamma-tocotrienol modulates total-body irradiation-induced hematopoietic injury in a nonhuman primate model. Int J Mol Sci. 2022;23:16170.
   PubMed Web of Science ®Google Scholar
• Vellichirammal NN, Sethi S, Pandey S, et al. Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation. Mol Ther Nucleic Acids. 2022;29:584–598.
   PubMedGoogle Scholar
• Fendler W, Malachowska B, Meghani K, et al. Evolutionarily conserved serum microRNAs predict radiation-induced fatality in nonhuman primates. Sci Transl Med. 2017;9:eaal2408.
   PubMed Web of Science ®Google Scholar
• Pannkuk EL, Laiakis EC, Fornace AJ Jr., et al. A metabolomic serum signature from nonhuman primates treated with a radiation countermeasure, gamma-tocotrienol, and exposed to ionizing radiation. Health Phys. 2018;115:3–11.
   PubMed Web of Science ®Google Scholar
• Cheema AK, Hinzman CP, Mehta KY, et al. Plasma derived exosomal biomarkers of exposure to ionizing radiation in nonhuman primates. Int J Mol Sci. 2018;19:3427.
   PubMed Web of Science ®Google Scholar
• Ghosh SP, Kulkarni S, Hieber K, et al. Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector. Int J Radiat Biol. 2009;85:598–606.
   PubMed Web of Science ®Google Scholar
• Berbee M, Fu Q, Boerma M, et al. gamma-Tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative stress after total-body irradiation by an HMG-CoA reductase-dependent mechanism. Radiat Res. 2009;171:596–605.
   PubMed Web of Science ®Google Scholar
• Rosen E, Fatanmi OO, Wise SY, et al. Gamma-tocotrienol, a radiation countermeasure, reverses proteomic changes in serum following total-body gamma irradiation in mice. Sci Rep. 2022;12:3387.
   PubMed Web of Science ®Google Scholar
• Berbee M, Fu Q, Boerma M, et al. Mechanisms underlying the radioprotective properties of gamma-tocotrienol: comparative gene expression profiling in tocol-treated endothelial cells. Genes Nutr. 2012;7:75–81.
   PubMed Web of Science ®Google Scholar
• Berbee M, Fu Q, Boerma M, et al. Reduction of radiation-induced vascular nitrosative stress by the vitamin E analog gamma-tocotrienol: evidence of a role for tetrahydrobiopterin. Int J Radiat Oncol Biol Phys. 2011;79:884–891.
   PubMed Web of Science ®Google Scholar
• Berbee M, Fu Q, Garg S, et al. Pentoxifylline enhances the radioprotective properties of gamma-tocotrienol: differential effects on the hematopoietic, gastrointestinal and vascular systems. Radiat Res. 2011;175:297–306.
   PubMed Web of Science ®Google Scholar
• Ray S, Kulkarni SS, Chakraborty K, et al. Mobilization of progenitor cells into peripheral blood by gamma-tocotrienol: a promising radiation countermeasure. Int Immunopharmacol. 2013;15:557–564.
   PubMed Web of Science ®Google Scholar
• Kulkarni S, Ghosh SP, Satyamitra M, et al. Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation. Radiat Res. 2010;173:738–747.
   PubMed Web of Science ®Google Scholar
• Singh VK, Fatanmi OO, Verma A, et al. Progenitor cell mobilization by gamma-tocotrienol: a promising radiation countermeasure. Health Phys. 2016;111:85–92.
   PubMed Web of Science ®Google Scholar
• Singh VK, Wise SY, Fatanmi OO, et al. Progenitors mobilized by gamma-tocotrienol as an effective radiation countermeasure. PLoS One. 2014;9:e114078.
   PubMed Web of Science ®Google Scholar
• Singh VK, Brown DS, Singh PK, et al. Progenitor cells as a bridging therapy for radiation casualties. Defence Sci J. 2011;61:118–124.
   Web of Science ®Google Scholar
• Singh VK, Brown DS, Kao TC, et al. Preclinical development of a bridging therapy for radiation casualties. Exp Hematol. 2010;38:61–70.
   PubMed Web of Science ®Google Scholar
• Singh VK, Wise SY, Singh PK, et al. Alpha-tocopherol succinate- and AMD3100-mobilized progenitors mitigate radiation-induced gastrointestinal injury in mice. Exp Hematol. 2012;40:407–417.
   PubMed Web of Science ®Google Scholar
• Garg S, Garg TK, Wise SY, et al. Effects of gamma-tocotrienol on intestinal injury in a GI-specific acute radiation syndrome model in nonhuman primate. Int J Mol Sci. 2022;23:4643.
   PubMed Web of Science ®Google Scholar
• Kulkarni S, Singh PK, Ghosh SP, et al. Granulocyte colony-stimulating factor antibody abrogates radioprotective efficacy of gamma-tocotrienol, a promising radiation countermeasure. Cytokine. 2013;62:278–285.
   PubMed Web of Science ®Google Scholar
• 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;184:644–651.
   PubMed Web of Science ®Google Scholar
• Banerjee S, Shah SK, Melnyk SB, et al. Cebpd Is essential for gamma-tocotrienol mediated protection against radiation-induced hematopoietic and intestinal injury. Antioxidants. 2018;7:55.
   Web of Science ®Google Scholar
• Pathak R, Bachri A, Ghosh SP, et al. The vitamin E analog gamma-tocotrienol (GT3) suppresses radiation-induced cytogenetic damage. Pharm Res. 2016;33:2117–2125.
   PubMed Web of Science ®Google Scholar
• 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 Dosimet. 2016;172:302–310.
   PubMed Web of Science ®Google Scholar
• Kulkarni S, Chakraborty K, Kumar KS, et al. Synergistic radioprotection by gamma-tocotrienol and pentoxifylline: role of cAMP signaling. ISRN Radiol. 2013;2013:390379.
   PubMedGoogle Scholar
• Ghosh SP, Pathak R, Kumar P, et al. Gamma-tocotrienol modulates radiation-induced microRNA expression in mouse spleen. Radiat Res. 2016;185:485–495.
   PubMed Web of Science ®Google Scholar
• Cheema AK, Mehta KY, Fatanmi OO, et al. A Metabolomic and lipidomic serum signature from nonhuman primates administered with a promising radiation countermeasure, gamma-tocotrienol. Int J Mol Sci. 2017;19:79.
   PubMed Web of Science ®Google Scholar
• Bernardes JP, Mishra N, Tran F, et al. Longitudinal multi-omics analyses identify responses of megakaryocytes, erythroid cells, and plasmablasts as hallmarks of severe COVID-19. Immunity. 2020;53(1296–314):e9.
   Google Scholar
• Cheema AK, Byrum SD, Sharma NK, et al. Proteomic changes in mouse spleen after radiation-induced injury and its modulation by gamma-tocotrienol. Radiat Res. 2018;190:449–463.
   PubMed Web of Science ®Google Scholar
• Singh VK, Seed TM, Cheema AK. Metabolomics-based predictive biomarkers of radiation injury and countermeasure efficacy: current status and future perspectives. Expert Rev Mol Diagn. 2021;21:641–654.
   PubMed Web of Science ®Google Scholar
• Singh VK, Newman VL, Romaine PL, et al. Use of biomarkers for assessing radiation injury and efficacy of countermeasures. Expert Rev Mol Diagn. 2016;16:65–81.
   PubMed Web of Science ®Google Scholar
• Singh VK, Simas M, Pollard H. Biomarkers for acute radiation syndrome: challenges for developing radiation countermeasures following animal rule. Expert Rev Mol Diagn. 2018;18:921–924.
   PubMed Web of Science ®Google Scholar
• Abuasal BS, Qosa H, Sylvester PW, et al. Comparison of the intestinal absorption and bioavailability of gamma-tocotrienol and alpha-tocopherol: in vitro, in situ and in vivo studies. Biopharm Drug Dispos. 2012;33:246–256.
   PubMed Web of Science ®Google Scholar
• Ledet GA, Biswas S, Kumar VP, et al. Development of orally administered gamma-tocotrienol (GT3) nanoemulsion for radioprotection. Int J Mol Sci. 2016;18:28.
   PubMed Web of Science ®Google Scholar
• Alqahtani S, Alayoubi A, Nazzal S, et al. Enhanced solubility and oral bioavailability of gamma-tocotrienol using a self-emulsifying drug delivery system (SEDDS). Lipids. 2014;49:819–829.
   PubMed Web of Science ®Google Scholar
• Aebersold P. FDA experience with medical countermeasures under the animal rule. Advances in preventive medicine. 2012;2012:507571.
   PubMedGoogle Scholar
• Allio T. Product development under FDA’s animal rule: understanding FDA’s expectations and potential implication for traditional development programs. Therapeutic Innovation and Regulatory Science. 2016;50:660–670.
   PubMed Web of Science ®Google Scholar
• U.S. Food and Drug Administration. Animal rule information. 2022. [Last accessed 2022 Oct 20]. Available at: http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMRegulatoryScience/ucm391604.htm
   Google Scholar
• U.S. Food and Drug Administration. Animal rule approvals. There is a list of all drugs approved by US FDA following Animal Rule. 2022. [Last accessed 2022 Dec 5]. Available at: https://www.fda.gov/drugs/nda-and-bla-approvals/animal-rule-approvals
   Google Scholar
• Singh VK, Romaine PL, Seed TM. Medical countermeasures for radiation exposure and related injuries: characterization of medicines, FDA-approval status and inclusion into the strategic national stockpile. Health Phys. 2015;108:607–630.
   PubMed Web of Science ®Google Scholar