Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates

Abstract

The search for treatments to counter potentially lethal radiation-induced injury over the past several decades has led to the development of multiple classes of radiation countermeasures. However, to date only granulocyte colony-stimulating factor (G-CSF; filgrastim, Neupogen)and pegylated G-CSF (pegfilgrastim, Neulasta) have been approved by the United States Food and Drug Administration (FDA) for the treatment of hematopoietic acute radiation syndrome (ARS). Gamma-tocotrienol (GT3) has demonstrated strong radioprotective efficacy in the mouse model, indicating the need for further evaluation in a large animal model. In this study, we evaluated GT3 pharmacokinetics (PK) and efficacy at different doses of cobalt-60 gamma radiation (0.6 Gy/min) using the nonhuman primate (NHP) model. The PK results demonstrated increased area under the curve with increasing drug dose and half-life of GT3. GT3 treatment resulted in reduced group mean neutropenia by 3-5 days and thrombocytopenia by 1-5 days. At 5.8 and 6.5 Gy total-body irradiation, GT3 treatment completely prevented thrombocytopenia. The capability of GT3 to reduce severity and duration of neutropenia and thrombocytopenia was dose dependent; 75 mg/kg treatment was more effective than 37.5 mg/kg treatment after a 5.8 Gy dose. However, the higher GT3 dose (75 mg/kg) was associated with higher frequency of adverse skin effects (small abscess) at the injection site. GT3 treatment of irradiated NHPs caused no significant difference in animal survival at 60 days postirradiation, however, low mortality was observed in irradiated, vehicle-treated groups as well. The data from this pilot study further elucidate the role and pharmacokinetics of GT3 in hematopoietic recovery after irradiation in a NHP model, and demonstrate the potential of GT3 as a promising radioprotector.

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.…”

“…Pre-irradiation and post-irradiation samples were paired for analysis of radiation-responsive miRNAs. Furthermore, to correlate the serum miRNAs with radiation impact, the radioprotective agent, GT3, was administered 24 h before irradiation in 24 macaques (13). Both GT3- and vehicle-treated groups were divided into 3 dose levels: 5.8 Gy (LD 30/60 ), 6.5 Gy (LD 50/60 ), and 7.2 Gy (LD 70/60 ).…”

The Potentiation of the Radioprotective Efficacy of Two Medical Countermeasures, Gamma-Tocotrienol and Amifostine, by a Combination Prophylactic Modality

“…Its antioxidant activity was a compelling reason to evaluate it for radioprotective efficacy; in recent years, it has received a great deal of attention by researchers and appears to be one of the most promising radioprotective tocols tested to date. Recent results suggest that GT3-stimulated granulocyte colony-stimulating factor (G-CSF) is involved in its radioprotective mechanism (6, 7) .…”

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

“…Promising radiation countermeasures under development for H-ARS have been tested in NHP for efficacy and pharmacokinetics/ pharmacodynamics. Some important radiation countermeasures tested for efficacy in the NHP model include G-CSF (filgrastim, Neupogen) (Farese et al 2013;, PEGylated G-CSF (PEGfilgrastim/Neulasta) (Hankey et al 2015), CBLB502 (Entolimod) (Krivokrysenko et al 2012(Krivokrysenko et al , 2015, interleukin-12 (HemaMax) (Basile et al 2012;GluzmanPoltorak et al 2014aGluzmanPoltorak et al , 2014b, AEOL 10150 (meso-porphyrin mimetic) (Garofalo et al 2014b), 5-Androstenediol (Stickney et al 2006(Stickney et al , 2007, amifostine (WR2721, Ethyol) (Geary et al 1989), B-190 (Vasin et al 2014) and c-tocotrienol (Singh et al 2016a). …”