Advanced Development of Gamma-Tocotrienol as a Radiation Countermeasure

The threat of a radiological attack on American cities (i.e., a 'dirty' bomb), or a nuclear accident, requires the development of a radiation countermeasure capable of protecting military personnel, who might have to enter a contaminated area, or capable of mitigating lethality in the general population. Although the search for suitable radiation countermeasures has been going on for the last 60 years, no safe and effective radiation countermeasure has been approved by the U.S. Food and Drug Administration (US FDA) for the acute radiation syndrome (ARS).

Exposure to ionizing radiation is a serious concern due to the deleterious effects of radiation on biological systems. These effects vary based on the dose absorbed and radiation quality. It is now well known that radiation exposure forms free radicals including superoxide, hydrogen peroxide, and hydroxyl radicals by the radiolysis of cellular aqueous milieu. The harmful effects of ionizing radiation are observed in almost all tissues, leading to multi-organ dysfunction syndrome. Wound inflictions along with radiation exposure are of even more serious concern because the immune system is extremely radiosensitive, which leaves individuals highly susceptible to opportunistic infections. Protection of hematopoietic tissue from acute radiation injury is an important criterion in developing radiation countermeasures. This need has prompted research among government laboratories, academic institutions, and pharmaceutical companies to identify potential radiation countermeasure candidates.

Several classes of radiation countermeasures have been investigated based on their ability to (a) reduce free radicals, (b) inhibit apoptosis, and (c) stimulate the hematopoietic system. These include several groups of compounds such as thiols and antioxidants, small-molecule apoptosis inhibitors, and cytokines. Although these approaches have led to several preclinical studies, not one of these candidate drugs has been approved by the US FDA to treat acute radiation syndrome.

Vitamin E is well known for its established health benefits, including antioxidant, neuroprotective, and anti-inflammatory properties. Vitamin E represents a family of compounds that act as important antioxidants that regulate peroxidation reactions and control free-radical production within the body. Vitamin E has eight different isoforms that belong to two categories: four saturated analogues (alpha, beta, gamma, and delta) called tocopherols and four unsaturated analogues referred to as tocotrienols. These eight components are collectively known as tocols. Tocols and their derivatives have been evaluated for their radioprotective properties. Gamma-tocotrienol (GT3) especially has shown promising radioprotective efficacy. At a dose of 200 mg/kg administered subcutaneously (sc) 24 hours before radiation exposure, the GT3 dose reduction factor was 1.29. GT3 also accelerated the recovery of total white blood cells, neutrophils, monocytes, platelets, and reticulocytes in irradiated mice, compared to vehicle-injected, irradiated controls. GT3 has been shown to protect hematopoietic stem cells as well as reduce instant and persistent DNA damage. Recently, GT3 radioprotective efficacy was confirmed in a pilot study using large animal model (nonhuman primates -- NHP). GT3 significantly mitigated radiation injury in NHP when administered in a single dose 24 hours before radiation exposure.

In the current project the main focus is to develop GT3 to mitigate the effects of radiation so that it can be approved by US FDA for human use. We will evaluate new formulations of GT3 to reduce its side effects and make it effective through oral route. We will conduct studies in NHP for efficacy of best formulation. We plan to study the effects of GT3 in NHP exposed to whole body as well as partial body radiation exposure to investigate its mechanism of action. Both hematopoietic and gastrointestinal systems of irradiated NHPs will be studied for beneficial effects of GT3.