title: Synergistic radioprotection by gamma-tocotrienol and pentoxifylline: role of cAMP signaling.
abstract: 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.
authors: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Scientific Research Department, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
authors: Shilpa
authors: S
authors: Kulkarni
authors: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Scientific Research Department, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
authors: Kushal
authors: K
authors: Chakraborty
authors: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Scientific Research Department, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
authors: K Sree
authors: KS
authors: Kumar
authors: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Scientific Research Department, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
authors: Tzu-Cheg
authors: TC
authors: Kao
authors: University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors: Martin
authors: M
authors: Hauer-Jensen
authors: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Scientific Research Department, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
authors: Sanchita P
authors: SP
authors: Ghosh