Pentoxifylline Enhances the Radioprotective Properties of γ-Tocotrienol: Differential Effects on the Hematopoietic, Gastrointestinal and Vascular Systems

Article (PDF Available)inRadiation Research 175(3):297-306 · March 2011with30 Reads
DOI: 10.1667/RR2399.1 · Source: PubMed
Abstract
The vitamin E analog γ-tocotrienol (GT3) is a potent radioprotector and mitigator. This study was performed to (a) determine whether the efficacy of GT3 can be enhanced by the addition of the phosphodiesterase inhibitor pentoxifylline (PTX) and (b) to obtain information about the mechanism of action. Mice were injected subcutaneously with vehicle, GT3 [400 mg/kg 24 h before total-body irradiation (TBI)], PTX (200 mg/kg 30 min before TBI), or GT3+PTX before being exposed to 8.5-13 Gy TBI. Overall lethality, survival time and intestinal, hematopoietic and vascular injury were assessed. Cytokine levels in the bone marrow microenvironment were measured, and the requirement for endothelial nitric oxide synthase (eNOS) was studied in eNOS-deficient mice. GT3+PTX significantly improved survival compared to GT3 alone and provided full protection against lethality even after exposure to 12.5 Gy. GT3+PTX improved bone marrow CFUs, spleen colony counts and platelet recovery compared to GT3 alone. GT3 and GT3+PTX increased bone marrow plasma G-CSF levels as well as the availability of IL-1α, IL-6 and IL-9 in the early postirradiation phase. GT3 and GT3+PTX were equally effective in ameliorating intestinal injury and vascular peroxynitrite production. Survival studies in eNOS-deficient mice and appropriate controls revealed that eNOS was not required for protection against lethality after TBI. Combined treatment with GT3 and PTX increased postirradiation survival over that with GT3 alone by a mechanism that may depend on induction of hematopoietic stimuli. GT3+PTX did not reduce GI toxicity or vascular oxidative stress compared to GT3 alone. The radioprotective effect of either drug alone or both drugs in combination does not require the presence of eNOS.

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Available from: Martin Hauer-Jensen
    • "GT3-mediated protection of intestinal cells occurs by downregulation of pro-apoptotic factors, as well by as upregulation of anti-apoptotic factors [120]. Furthermore, GT3 treatment combined with PTX increased post-irradiation survival over that of GT3 alone by a mechanism that may depend on the induction of hematopoietic stimuli [91]. Though much is known about the potential mechanism by which GT3 works as a radioprotector, there are ongoing investigations to further determine the mechanisms by which single injections of GT3 elicit such a powerful radioprotective response. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · May 2016
    • "Indeed, the combination of í µí»¾T3 and pentoxifylline significantly improved the survival of irradiated mice after exposure to doses as high as 12 Gy by increasing the number of bone marrow colony-forming units and spleen colonies and hastening platelet recovery [127]. However, the combination treatment was no more effective than í µí»¾T3 alone in terms of protecting against GI injury or reducing vascular peroxynitrite production [127]. Advancement of í µí»¾T3 as a radiation countermeasure for human use will require documentation of its pharmacokinetics, pharmacodynamics, and radioprotective efficacy in nonhuman primate models. "
    [Show abstract] [Hide abstract] ABSTRACT: The potentially life-threatening effects of total body ionizing radiation exposure have been known for more than a century. Despite considerable advances in our understanding of the effects of radiation over the past six decades, efforts to identify effective radiation countermeasures for use in case of a radiological/nuclear emergency have been largely unsuccessful. Vitamin E is known to have antioxidant properties capable of scavenging free radicals, which have critical roles in radiation injuries. Tocopherols and tocotrienols, vitamin E analogs together known as tocols, have shown promise as radioprotectors. Although the pivotal mechanisms of action of tocols have long been thought to be their antioxidant properties and free radical scavenging activities, other alternative mechanisms have been proposed to drive their activity as radioprotectors. Here we provide a brief overview of the effects of ionizing radiation, the mechanistic mediators of radiation-induced damage, and the need for radiation countermeasures. We further outline the role for, efficacy of, and mechanisms of action of tocols as radioprotectors, and we compare and contrast their efficacy and mode of action with that of another well-studied chemical radioprotector, amifostine.
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    • "In addition, γ-and δ-tocotrienols may mediate their protective effects in radiation injury in part by inhibition of 3-hydroxy-3- methyl-glutaryl-CoA reductase [18,22,23]. PTX enhanced the radioprotective properties of γ-tocotrienol in a combined administration before whole body irradiation [24]. This study aimed to identify the effects of PTX alone on cardiac radiation injury, and to investigate the effects of PTX when administered in combination with tocotrienols. "
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