Purpose. This study was designed to determine the efficacy and mechanisms of radioprotection by the combination of gamma-tocotrienol (GT3) and pentoxifylline (PTX) against acute radiation injury. Materials and Methods. Post-irradiation survival was monitored to determine the most efficacious dose and time of administration of PTX. Dose reduction factor (DRF) was calculated to compare the radioprotective efficacy of the combination. To determine the mechanism of synergistic radioprotection by the combination, mevalonate or calmodulin were coadministered with the GT3-PTX combination. Mevalonate was used to reverse the inhibitory effect of GT3 on 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), and calmodulin was used to reverse the inhibition of phosphodiesterase (PDE) by PTX. Results. The combination was most effective when 200？mg/kg of PTX was administered 15？min before irradiation along with 200？mg/kg of GT3 (？24？h) and resulted in a DRF of 1.5. White blood cells and neutrophil counts showed accelerated recovery in GT3-PTX-treated groups compared to GT3. Mevalonate had no effect on the radioprotection of GT3-PTX; calmodulin abrogated the synergistic radioprotection by GT3-PTX. Conclusion. The mechanism of radioprotection by GT3-PTX may involve PDE inhibition. 1. Introduction Exposure to lethal dose of ionizing radiation can lead to acute radiation syndrome (ARS), which is a combination of bone marrow, gastrointestinal, and cardiovascular-neuronal subsyndromes. These subsyndromes occur within hours to days based on the radiosensitivity of the tissue and the dose absorbed, and can be potentially life threatening [1]. Due to increased threat of nuclear fallout from terrorist activities and accidents at the nuclear power plants, major efforts are being invested in the development of radiation countermeasures to protect first responder military personnel and civilians [2]. Exposure to ionizing radiation is also a major concern in cancer patients undergoing radiation therapy [3]. However, no drug has been approved by Food and Drug Administration (FDA) to be used in humans against ARS. Radiation-induced toxicity in various tissues is a manifestation of free radical generation, oxidative stress, DNA damage [4], inflammation, [5], and apoptotic signaling [6]. These signaling pathways are known to have deleterious effects in various diseases such as hypertension, diabetes, and cancer progression [5, 7]; therefore agents that have beneficial roles in modulating such signaling pathways may play important role in alleviating radiation-induced injury [8]. Various
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