Radioprotective Effects of Amifostine on Acute and Chronic Esophageal Injury in Rodents

Vujašković, Željko; Thrasher, Bradley A.; Jackson, Isabel L.; Brizel, Marla B.; Brizel, D.M.

doi:10.1016/j.ijrobp.2007.05.062

Cited by 12 publications

(7 citation statements)

References 32 publications

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“…Amifostine, a classical example of a radioprotective agent, scavenges ROS and protects cells from radiation damage 27–29 . Amifostine has been used to reduce chronic toxicities, as shown in several studies 30–32 .…”

Section: Discussionmentioning

confidence: 99%

HISTOPATHOLOGICAL AND SCINTIGRAPHIC COMPARISONS OF THE PROTECTIVE EFFECTS OF l‐CARNITINE AND AMIFOSTINE AGAINST RADIATION‐INDUCED LATE RENAL TOXICITY IN RATS

Çaloğlu

Yurut-Caloglu

Durmuş-Altun

et al. 2009

Clin Exp Pharma Physio

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1. The aim of the present study was to compare the protective effects of L-carnitine and amifostine against radiation-induced late nephrotoxicity using technetium-99m diethylenetriaminepentaacetic acid scintigraphy and histopathological examination. 2. Seventy-one Albino rats were randomly divided into six groups as follows: (i) AMI + RAD (n = 15), 200 mg/kg, i.p., amifostine 30 min prior to irradiation (a single dose of 9 Gy); (ii) LC + RAD (n = 15), 300 mg/kg, i.p., L-carnitine 30 min prior to irradiation; (iii) LC (n = 10), 300 mg/kg, i.p., L-carnitine 30 min prior to sham irradiation; (iv) AMI (n = 10), 200 mg/kg, i.p., amifostine 30 min prior to sham irradiation; RAD (n = 11), 1 mL/kg, i.p., normal saline 30 min prior to irradiation; and (vi) control (n = 10), 1 mL/kg, i.p., normal saline 30 min prior to sham irradiation. Scintigraphy was performed before treatment and again 6 months after treatment. Kidneys were examined by light microscopy and a histopathological scoring system was used to assess the degree of renal damage. 3. The main histopathological findings were proximal tubular damage and interstitial fibrosis. Glomerular injury was similar in all groups. Tubular degeneration and atrophy were less common in the AMI + RAD group than in the RAD group (P = 0.011 and P = 0.015, respectively), as well as in the LC + RAD group compared with the RAD group (P = 0.028 and P = 0.036, respectively). Interstitial fibrosis in the AMI + RAD and LC + RAD groups was significantly less than that in the RAD group (P = 0.015 and P = 0.015, respectively). The highest total renal injury score (9) was seen in the RAD group. On scintigraphy, there were significant differences in post-treatment time to peak count (T(max)) and time from peak count to half count (T((1/2))) values (P = 0.01 and 0.02, respectively) between groups in the right kidney. In the control and RAD groups, the T((1/2)) of the right kidney was 8 +/- 2 and 21 +/- 2 min, respectively. The T(max) values for the AMI + RAD and LC + RAD groups (2.8 +/- 0.2 and 3.2 +/- 0.2 min, respectively) were similar to those in the control group (2.5 +/- 0.3 min). 4. Based on the results of the present study, L-carnitine and amifostine have comparable and significant protective effects against radiation-induced late nephrotoxicity.

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Section: Discussionmentioning

confidence: 99%

HISTOPATHOLOGICAL AND SCINTIGRAPHIC COMPARISONS OF THE PROTECTIVE EFFECTS OF l‐CARNITINE AND AMIFOSTINE AGAINST RADIATION‐INDUCED LATE RENAL TOXICITY IN RATS

Çaloğlu

Yurut-Caloglu

Durmuş-Altun

et al. 2009

Clin Exp Pharma Physio

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“…Male C57BL/J6 mice (Jackson Labs, Bar Harbor, ME, USA) were irradiated as previously described [ 64 ]. Mice at approximately 10–12 weeks weighing ≥20 g were anesthetized by i.p.…”

Section: Methodsmentioning

confidence: 99%

Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways

Sabirzhanov

Makarevich

Barrett

et al. 2020

IJMS

Self Cite

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Radiotherapy for brain tumors induces neuronal DNA damage and may lead to neurodegeneration and cognitive deficits. We investigated the mechanisms of radiation-induced neuronal cell death and the role of miR-711 in the regulation of these pathways. We used in vitro and in vivo models of radiation-induced neuronal cell death. We showed that X-ray exposure in primary cortical neurons induced activation of p53-mediated mechanisms including intrinsic apoptotic pathways with sequential upregulation of BH3-only molecules, mitochondrial release of cytochrome c and AIF-1, as well as senescence pathways including upregulation of p21WAF1/Cip1. These pathways of irradiation-induced neuronal apoptosis may involve miR-711-dependent downregulation of pro-survival genes Akt and Ang-1. Accordingly, we demonstrated that inhibition of miR-711 attenuated degradation of Akt and Ang-1 mRNAs and reduced intrinsic apoptosis after neuronal irradiation; likewise, administration of Ang-1 was neuroprotective. Importantly, irradiation also downregulated two novel miR-711 targets, DNA-repair genes Rad50 and Rad54l2, which may impair DNA damage responses, amplifying the stimulation of apoptotic and senescence pathways and contributing to neurodegeneration. Inhibition of miR-711 rescued Rad50 and Rad54l2 expression after neuronal irradiation, enhancing DNA repair and reducing p53-dependent apoptotic and senescence pathways. Significantly, we showed that brain irradiation in vivo persistently elevated miR-711, downregulated its targets, including pro-survival and DNA-repair molecules, and is associated with markers of neurodegeneration, not only across the cortex and hippocampus but also specifically in neurons isolated from the irradiated brain. Our data suggest that irradiation-induced miR-711 negatively modulates multiple pro-survival and DNA-repair mechanisms that converge to activate neuronal intrinsic apoptosis and senescence. Using miR-711 inhibitors to block the development of these regulated neurodegenerative pathways, thus increasing neuronal survival, may be an effective neuroprotective strategy.

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“…Nineteen articles reported evidence of chronic oxidative stress by our criteria (13–32). The tissues in which this was shown included brain (13,21,22,25,27), aorta (28), esophagus (32), lung (15–17,19,23,24,29), kidney (20), liver (14,26,30,31), and prostate (18), at times ranging from 1 day to 6 weeks or more after irradiation (figure 1). In each of these reports, evidence of chronic OS appeared to precede evidence of tissue injury.…”

Section: Resultsmentioning

confidence: 99%

Chronic oxidative stress after irradiation: An unproven hypothesis

Cohen

2013

Medical Hypotheses

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Injury and organ failure after irradiation of late-responding tissues is a substantial problem in radiation oncology and a major threat after accidental or belligerent exposures. The mechanisms of injury may include death of clonogens, vascular injury, activation of cytokine networks, and/or chronic oxidative stress. Knowledge of mechanisms may guide optimal use of mitigators. The hypothesis of chronic oxidative stress as a mechanism of late radiation injury has received much attention. We review herein the published evidence for chronic oxidative stress in vivo, and for use of antioxidants as mitigators of normal tissue radiation injury. We conclude that there is only indirect evidence for chronic oxidative stress after irradiation, and there are only limited published reports of mitigation by antioxidants. We did not find a differentiation of persistent markers of oxidative stress from an ongoing production of oxygen radicals. It is thus unproven that chronic oxidative stress plays a major role in causing radiation injury and organ failure in late-responding tissues. Further investigation is justified, to identify persistent oxidative stress and to identify optimal mitigators of radiation injury.

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Radioprotective Effects of Amifostine on Acute and Chronic Esophageal Injury in Rodents

Cited by 12 publications

References 32 publications

HISTOPATHOLOGICAL AND SCINTIGRAPHIC COMPARISONS OF THE PROTECTIVE EFFECTS OF l‐CARNITINE AND AMIFOSTINE AGAINST RADIATION‐INDUCED LATE RENAL TOXICITY IN RATS

HISTOPATHOLOGICAL AND SCINTIGRAPHIC COMPARISONS OF THE PROTECTIVE EFFECTS OF l‐CARNITINE AND AMIFOSTINE AGAINST RADIATION‐INDUCED LATE RENAL TOXICITY IN RATS

Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways

Chronic oxidative stress after irradiation: An unproven hypothesis

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