title: 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.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA. vijay.singh@usuhs.edu.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare Systems, Little Rock, AR 72205, USA. mhjensen@uams.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
mesh_terms: D054508:Acute Radiation Syndrome / Q000188:drug therapy* / Q000517:prevention & control; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009504:Neutrophils / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002839:Chromans; D016207:Cytokines; D011837:Radiation-Protective Agents; D014810:Vitamin E; C013649:plastochromanol 8
keywords: granulocyte colony-stimulating factor; mice; neutropenia; nonhuman primates; radiation; thrombocytopenia; γ-tocotrienol