Mechanism of radioprotection by <i>δ</i>-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways

Satyamitra, Merriline M.; Ney, Patrick H.; Graves, John; Mullaney, Conor; Srinivasan, Vijaya

doi:10.1259/bjr/63355844

Cited by 31 publications

(41 citation statements)

References 35 publications

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“…Radiotherapy, second only to surgery, is used with 80% of patients as one of the most effective modalities for the treatment and cure of neoplastic diseases (Nair et al, 2001;Parihar et al, 2007;Satyamitra et al, 2012). Ionizing radiation triggers a series of events starting from generation of reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

et al. 2015

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Radiotherapy, a therapeutic modality of cancer treatment, nonselectively damages normal tissues as well as tumor tissues. The search is ongoing for therapeutic agents that selectively reduce radiation-induced normal tissue injury without reducing tumoricidal effect, thereby increasing the therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2ʹ-(3,4-dimethoxyphenyl)-59benzimidazolyl] benzimidazole (DMA) as noncytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose-reduction factor of 1.28. An oxygen radical absorbing capacity assay confirmed its freeradical quenching ability. Single bolus dose and 28-days of repeated administration of DMA in mice for toxicity studies determined an LD 50 of .2000 mg/kg body weight (bw) and 225 mg/kg bw, respectively, suggesting DMA is safe. Histopathology, biochemical parameters, and relative organ weight analysis revealed insignificant changes in the DMA-treated animals. The pharmacokinetic study of DMA at oral and intravenous doses showed its C max 5 1 hour, bioavailability of 8.84%, elimination half-life of 4 hours, and an enterohepatic recirculation. Biodistribution study in mice with Ehrlich ascites tumors showed that 99m Tc-DMA achieved its highest concentration in 1 hour and was retained up to 4 hours in the lungs, liver, kidneys, and spleen, and in a low concentration in the tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that the single-dose treatment of tumor-bearing mice with DMA 2 hours before 8 Gy total body irradiation showed an impressive rescue of radiation-induced morbidity in terms of weight loss and mortality without a change in tumor response.

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Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

et al. 2015

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“…These changes are associated with activation of mRNA translation regulator eIF4E and ribosomal protein S6, which are responsible for cell survival and growth. DT3 has also been shown to suppress apoptotic death pathways and modulate autophagic markers (Satyamitra et al, 2012). Further study is needed to understand exact mechanism of G-CSF induction by DT3.…”

Section: Discussionmentioning

confidence: 99%

“…DT3 has been shown to have both radioprotective (administered before radiation exposure) and radiomitigative (administered after radiation exposure) efficacy (Satyamitra et al, 2011). Recently, delta-tocotrienol (DT3) was demonstrated to reduce activation of caspase-8, caspase-3, and caspase-7 while increasing autophagy-related beclin-1 expression in irradiated bone marrow cells (Satyamitra et al, 2012). DT3 also has been reported to increase cell survival and regeneration of hematopoietic microfoci and lineage -/Sca-1 + /c-Kit + stem and progenitor cells in irradiated mouse bone marrow cells (Li et al, 2010).…”

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confidence: 99%

Radioprotective efficacy of delta-tocotrienol, a vitamin E isoform, is mediated through granulocyte colony-stimulating factor

Singh

Wise²,

Scott³

et al. 2014

Life Sciences

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Newman, Victoria L.; and Fatanmi, Oluseyi O., "Radioprotective efficacy of delta-tocotrienol, a vitamin E isoform, is mediated through granulocyte colony-stimulating factor" (2014 Aims: The objectives of this study were to determine the cytokine induction by delta tocotrienol (DT3, a promising radiation countermeasure) and to investigate the role of granulocyte colony-stimulating factor (G-CSF) in its radioprotective efficacy against ionizing radiation in mice. Main methods:Multiplex Luminex was used to analyze cytokines induced by DT3 and other tocols (gammatocotrienol and tocopherol succinate) in CD2F1 mice. Mice were injected with an optimal dose of DT3 and a G-CSF antibody, and their 30-day survival against cobalt-60 gamma-irradiation was monitored. The neutralization of G-CSF by the administration of a G-CSF-specific antibody in DT3-injected mice was investigated by multiplex Luminex. Key findings: Our data demonstrate that DT3 induced high levels of various cytokines comparable to other tocols being developed as radiation countermeasures. DT3 significantly protected mice against ionizing radiation, and the administration of a G-CSF neutralizing antibody to DT3-treated animals resulted in the complete abrogation of DT3's radioprotective efficacy and neutralization of G-CSF in peripheral blood. Significance: Our study findings suggest that G-CSF induced by DT3 mediates its radioprotective efficacy against ionizing radiation in mice.Published by Elsevier Inc.

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“…Pharmacokinetics of DT3 was evaluated previously in CD2F1 mice. 21 Authors determined the plasma concentration of a single dose of DT3 (300 mg/kg) administered sc in CD2F1 mice. The peak plasma concentration (C max ) of DT3 was 195 mmol/L 1 hour after injection (T max ).…”

Section: Introductionmentioning

confidence: 99%

“…The plasma half-life (t 1/2 ) was 1.8 hours, and DT3 was cleared from plasma within 12 hours after administration. 21 Gamma-tocotrienol (GT3, Figure 1B) also exhibits potent radioprotective activity following whole-body g-radiation exposure in a mouse model. It was previously demonstrated that GT3 provided higher radioprotection than alpha-tocopherol.…”

Section: Introductionmentioning

confidence: 99%

Acute Toxicity of Subcutaneously Administered Vitamin E Isomers Delta- and Gamma-Tocotrienol in Mice

et al. 2014

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The toxicity of parenterally administered vitamin E isomers, delta-tocotrienol (DT3) and gamma-tocotrienol (GT3), was evaluated in male and female CD2F1 mice. In an acute toxicity study, a single dose of DT3 or GT3 was administered subcutaneously in a dose range of 200 to 800 mg/kg. A mild to moderately severe dermatitis was observed clinically and microscopically in animals at the injection site at doses above 200 mg/kg. The severity of the reaction was reduced when the drug concentration was lowered. Neither drug produced detectable toxic effects in any other tissue at the doses tested. Based on histopathological analysis for both DT3 and GT3, and macroscopic observations of inflammation at the injection site, a dose of 300 mg/kg was selected as the lowest toxic dose in a 30-day toxicity study performed in male mice. At this dose, a mild skin irritation occurred at the injection site that recovered completely by the end of the experimental period. At a dose of 300 mg/kg of DT3 or GT3, no adverse effects were observed in any tissues or organs.

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Mechanism of radioprotection by δ-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways

Cited by 31 publications

References 35 publications

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

Preclinical Evaluation of DMA, a Bisbenzimidazole, as Radioprotector: Toxicity, Pharmacokinetics, and Biodistribution Studies in Balb/c Mice

Radioprotective efficacy of delta-tocotrienol, a vitamin E isoform, is mediated through granulocyte colony-stimulating factor

Acute Toxicity of Subcutaneously Administered Vitamin E Isomers Delta- and Gamma-Tocotrienol in Mice

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