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

Singh, Vijay K.; Seed, Thomas M.

doi:10.1080/13543784.2023.2169127

Cited by 15 publications

(17 citation statements)

References 68 publications

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“…Therefore, protecting and rescuing HSCs from radiation damage is not only critical for normal hematopoietic system function, but is also critical for the survival of cancer patients undergoing radiotherapy and for the development of MCMs (63)(64)(65). We have shown GT3 as a promising MCM with significant radioprotective efficacy both in mice and NHPs (31,34,39,66,67). GT3 is currently under advanced development for H-ARS (34).…”

Section: Discussionmentioning

confidence: 99%

“…GT3, a potent antioxidant and a promising radioprotector ( 25 , 31 , 67 ), is under advanced development as a radioprotective prophylaxis MCM for H-ARS ( 34 ). Importantly, it has been observed that a single injection of GT3, compared to multiple doses of Neupogen/Leukine and two doses of Neulasta (with supportive care including blood products) was found to be equally effective (without supportive care/ blood products) in ameliorating hematopoietic injury in an NHP model ( 31 , 34 , 67 , 75 , 76 ). Moreover, the radioprotective properties of GT3 relies not only on its free radical scavenging properties, but also on its ability to accumulate 30 – 50 times higher in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

Garg,

Miousse

et al. 2023

Radiation Research

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Currently, no radioprotectors have been approved to mitigate hematopoietic injury after exposure to ionizing radiation. Acute ionizing radiation results in damage to both hematopoietic and immune system cells. Pre-exposure prophylactic agents are needed for first responders and military personnel. In this study, the ability of gamma-tocotrienol (GT3), a promising radioprotector and antioxidant, to ameliorate partial-body radiation-induced damage to the hematopoietic compartment was evaluated in a nonhuman primate (NHP) model. A total of 15 rhesus NHPs were divided into two groups, and were administered either GT3 or vehicle 24 h prior to 4 or 5.8 Gy partial-body irradiation (PBI), with 5% bone marrow (BM) sparing. Each group consisted of four NHPs, apart from the vehicle-treated group exposed to 5.8 Gy, which had only three NHPs. BM samples were collected 8 days prior to irradiation in addition to 2, 7, 14, and 30 days postirradiation. To assess the clonogenic ability of hematopoietic stem and progenitor cells (HSPCs), colony forming unit (CFU) assays were performed, and lymphoid cells were immunophenotyped using flow cytometry. As a result of GT3 treatment, an increase in HSPC function was evident by an increased recovery of CFU-granulocyte macrophages (CFU-GM). Additionally, GT3 treatment was shown to increase the percentage of CD34+ cells, including T and NK-cell subsets. Our data further affirm GT3’s role in hematopoietic recovery and suggest the need for its further development as a prophylactic radiation medical countermeasure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

Garg,

Miousse

et al. 2023

Radiation Research

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“…For example, several studies have shown that γ-tocotrienol (γGT3), a saturated vitamer of vitamin E, exerts protective effects on hematopoietic stem cells and intestinal crypt cells in the gastrointestinal tract in murine and nonhuman primate (NHP) models, accelerating recovery from IR-induced injury at various doses (5.8, 6.5, 11, or 12 Gy). [24][25][26][27][28][29][30][31] The radioprotector, indralin (B-190), was also shown to exhibit radioprotective effects on hematopoietic and other tissues, including the intestines, skin, testes, and salivary glands, and it improved survival rates in monkeys after total-body irradiation (TBI) at a dose of 6.8 Gy. [32][33][34][35][36] BIO300, a suspension of synthetic genistein nanoparticles, was developed by the Humanetics Corporation to prevent and mitigate the effects of ARS and DEARE, and radioprotective effects have been demonstrated in mice and NHPs.…”

Section: The Mechanism Of Ir-induced Injurymentioning

confidence: 99%

“…Some antioxidants are being investigated as radioprotective agents for ARS. For example, several studies have shown that γ‐tocotrienol (γGT3), a saturated vitamer of vitamin E, exerts protective effects on hematopoietic stem cells and intestinal crypt cells in the gastrointestinal tract in murine and nonhuman primate (NHP) models, accelerating recovery from IR‐induced injury at various doses (5.8, 6.5, 11, or 12 Gy) 24–31 . The radioprotector, indralin (B‐190), was also shown to exhibit radioprotective effects on hematopoietic and other tissues, including the intestines, skin, testes, and salivary glands, and it improved survival rates in monkeys after total‐body irradiation (TBI) at a dose of 6.8 Gy 32–36 .…”

Section: Advancement In the Development Of Radioprotective Agentsmentioning

confidence: 99%

Development of radiation countermeasure agents for acute radiation syndromes

Guan,

Li,

Meng

2023

Anim Models and Exp Med

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The risk of internal and external exposure to ionizing radiation (IR) has increased alongside the development and implementation of nuclear technology. Therefore, serious security issues have emerged globally, and there has been an increase in the number of studies focusing on radiological prevention and medical countermeasures. Radioprotective drugs are particularly important components of emergency medical preparedness strategies for the clinical management of IR‐induced injuries. However, a few drugs have been approved to date to treat such injuries, and the related mechanisms are not entirely understood. Thus, the aim of the present review was to provide a brief overview of the World Health Organization's updated list of essential medicines for 2023 for the proper management of national stockpiles and the treatment of radiological emergencies. This review also discusses the types of radiation‐induced health injuries and the related mechanisms, as well as the development of various radioprotective agents, including Chinese herbal medicines, for which significant survival benefits have been demonstrated in animal models of acute radiation syndrome.

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“…One potential radiation MCM under advanced development as a pre-exposure prophylaxis for H-ARS is gamma-tocotrienol (GT3), a component of vitamin E [ 7 ]. GT3 is an antioxidant as well as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and has proven radioprotective efficacy in both mice and nonhuman primates (NHPs) when administered 24 h prior to total-body irradiation (TBI) [ 8 – 12 ]. Its dose reduction factor in mice is 1.29 when administered 24 h prior to irradiation at a dose of 200 mg/kg [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptome profile changes in the jejunum of nonhuman primates exposed to supralethal dose of total- or partial-body radiation

et al. 2023

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The risk of exposure of the general public or military personnel to high levels of ionizing radiation from nuclear weapons or radiological accidents is a dire national security matter. The development of advanced molecular biodosimetry methods, those that measure biological response, such as transcriptomics, to screen large populations of radiation-exposed victims is key to improving survival outcomes during radiological mass casualty scenarios. In this study, nonhuman primates were exposed to either 12.0 Gy cobalt-60 gamma (total-body irradiation, TBI) or X-ray (partial-body irradiation, PBI) 24 h after administration of a potential radiation medical countermeasure, gamma-tocotrienol (GT3). Changes in the jejunal transcriptomic profiles in GT3-treated and irradiated animals were compared to healthy controls to assess the extent of radiation damage. No major effect of GT3 on radiation-induced transcriptome at this radiation dose was identified. About 80% of the pathways with a known activation or repression state were commonly observed between both exposures. Several common pathways activated due to irradiation include FAK signaling, CREB signaling in the neurons, phagosome formation, and G-protein coupled signaling pathway. Sex-specific differences associated with excessive mortality among irradiated females were identified in this study, including Estrogen receptor signaling. Differential pathway activation was also identified across PBI and TBI, pointing towards altered molecular response for different degrees of bone marrow sparing and radiation doses. This study provides insight into radiation-induced changes in jejunal transcriptional profiles, supporting the investigation for the identification of biomarkers for radiation injury and countermeasure efficacy.

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

Cited by 15 publications

References 68 publications

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

Development of radiation countermeasure agents for acute radiation syndromes

Transcriptome profile changes in the jejunum of nonhuman primates exposed to supralethal dose of total- or partial-body radiation

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