γ-Tocotrienol as a Promising Countermeasure for Acute Radiation Syndrome: Current Status

Abstract

The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of non-toxic, safe and effective medical countermeasures for radiological and nuclear emergency. To date, the U.S. Food and Drug Administration (U.S. FDA) has approved only two growth factors, Neupogen (granulocyte colony-stimulating factor (G-CSF), filgrastim) and Neulasta (PEGylated G-CSF, pegfilgrastim) for the treatment of hematopoietic acute radiation syndrome (H-ARS) following the Animal Efficacy Rule. Promising radioprotective efficacy results of γ-tocotrienol (GT3; a member of the vitamin E family) in the mouse model encouraged its further evaluation in the nonhuman primate (NHP) model. These studies demonstrated that GT3 significantly aided the recovery of radiation-induced neutropenia and thrombocytopenia compared to the vehicle controls; these results particularly significant after exposure to 5.8 or 6.5 Gray (Gy) whole body γ-irradiation. The stimulatory effect of GT3 on neutrophils and thrombocytes (platelets) was directly and positively correlated with dose; a 75 mg/kg dose was more effective compared to 37.5 mg/kg. GT3 was also effective against 6.5 Gy whole body γ-irradiation for improving neutrophils and thrombocytes. Moreover, a single administration of GT3 without any supportive care was equivalent, in terms of improving hematopoietic recovery, to multiple doses of Neupogen and two doses of Neulasta with full supportive care (including blood products) in the NHP model. GT3 may serve as an ultimate radioprotector for use in humans, particularly for military personnel and first responders. In brief, GT3 is a promising radiation countermeasure that ought to be further developed for U.S. FDA approval for the ARS indication.

Evolutionarily conserved serum microRNAs predict radiation-induced fatality in nonhuman primates

“…3I). The mechanism of GT3’s radioprotective efficacy in NHPs remains unclear, but, as published previously, GT3 boosts the recovery of the hematopoietic system after TBI (13) However, because GT3 also increases C-reactive protein (CRP) concentration after irradiation, the differential impact on radiation-associated miRNAs may be due to a complex biological function of GT3 (12). Unexpectedly, the impact of GT3 on miR-133b and miR-215 expression after irradiation outweighed that on miR-375, which allowed the model to maintain its 100% diagnostic accuracy for separating irradiated GT3-treated macaques from any of the pre-irradiation samples (fig.…”

The efficacy and safety of amifostine for the acute radiation syndrome

“…GT3 is currently under advanced development as a radiation countermeasure [112]. Optimal radioprotective doses of GT3 for acutely, potentially lethally irradiated mice have been estimated to be 200 mg/kg [113].…”

Radiation Countermeasures: Current Status

“…It reduces the mortality rate caused due to radiation induced hematopoietic syndrome by recovery in neutropenia and thrombocytopenia and is also found effective against GI syndrome. Compared to multiple doses of Neupogen and neulasta, GT3 is effective in a single dose without any supportive care in NHP 21 . The precise mechanism of radioprotection by GT3 is not well known but it provides protection against radiation by upregulating the expression of G-CSF, interleukin IL-1α, IL-1β, IL-6, IL-17, macrophage inflammatory protein within 24 h of administration of the drug 22,23 .…”