Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates

Vijay K. Singh, Shilpa Kulkarni, Oluseyi O. Fatanmi, Stephen Y. Wise, Victoria L. Newman, Patricia L P Romaine, Howard Hendrickson, Jatinder Gulani, Sanchita P. Ghosh, K. Sree Kumar, Martin Hauer-Jensen

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)285-298
Number of pages14
JournalRadiation Research
Volume185
Issue number3
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

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primates
Primates
Granulocyte Colony-Stimulating Factor
dosage
Pharmacokinetics
Neutropenia
Thrombocytopenia
Therapeutics
Acute Radiation Syndrome
radiation
cobalt 60
Radiation Injuries
animal models
irradiation
countermeasures
Whole-Body Irradiation
mortality
Gamma Rays
United States Food and Drug Administration
Cobalt

ASJC Scopus subject areas

  • Biophysics
  • Radiation
  • Medicine(all)
  • Radiology Nuclear Medicine and imaging

Cite this

Singh, V. K., Kulkarni, S., Fatanmi, O. O., Wise, S. Y., Newman, V. L., Romaine, P. L. P., ... Hauer-Jensen, M. (2016). Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates. Radiation Research, 185(3), 285-298. https://doi.org/10.1667/RR14127.1

Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates. / Singh, Vijay K.; Kulkarni, Shilpa; Fatanmi, Oluseyi O.; Wise, Stephen Y.; Newman, Victoria L.; Romaine, Patricia L P; Hendrickson, Howard; Gulani, Jatinder; Ghosh, Sanchita P.; Kumar, K. Sree; Hauer-Jensen, Martin.

In: Radiation Research, Vol. 185, No. 3, 01.03.2016, p. 285-298.

Research output: Contribution to journalArticle

Singh, VK, Kulkarni, S, Fatanmi, OO, Wise, SY, Newman, VL, Romaine, PLP, Hendrickson, H, Gulani, J, Ghosh, SP, Kumar, KS & Hauer-Jensen, M 2016, 'Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates', Radiation Research, vol. 185, no. 3, pp. 285-298. https://doi.org/10.1667/RR14127.1
Singh VK, Kulkarni S, Fatanmi OO, Wise SY, Newman VL, Romaine PLP et al. Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates. Radiation Research. 2016 Mar 1;185(3):285-298. https://doi.org/10.1667/RR14127.1
Singh, Vijay K. ; Kulkarni, Shilpa ; Fatanmi, Oluseyi O. ; Wise, Stephen Y. ; Newman, Victoria L. ; Romaine, Patricia L P ; Hendrickson, Howard ; Gulani, Jatinder ; Ghosh, Sanchita P. ; Kumar, K. Sree ; Hauer-Jensen, Martin. / Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates. In: Radiation Research. 2016 ; Vol. 185, No. 3. pp. 285-298.
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