Use of Amifostine, a Novel Cytoprotective, in α-Amanitin Poisoning

Wills, Brandon K.; Haller, Nairmeen; Peter, David J.; White, Lynn J.

doi:10.1081/clt-66079

Cited by 6 publications

(7 citation statements)

References 29 publications

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“…The functions of IGFBP1 reported here provide a reasonable explanation for the lack of p53 mitochondrial accumulation or apoptosis induction reported previously for livers of mice following exposure to ␥-irradiation (Erster et al 2004). In contrast to such DNA damaging agents, ␣-amanitin has been shown to inhibit transcription and to elicit apoptosis in hepatocytes both in vitro and in vivo (Leist et al 1994;Hentze et al 2004;Wills et al 2005;Zhao et al 2006). This compound is the primary toxicological amatoxin in the "death cap" mushroom Amanita phalloides, and liver is one of the most sensitive organs to ␣-amanitin poisoning (Wills et al 2005;Zhao et al 2006).…”

Section: ␣-Amanitin Induces P53-mediated Mitochondrial Apoptosis In Lmentioning

confidence: 67%

“…In contrast to such DNA damaging agents, ␣-amanitin has been shown to inhibit transcription and to elicit apoptosis in hepatocytes both in vitro and in vivo (Leist et al 1994;Hentze et al 2004;Wills et al 2005;Zhao et al 2006). This compound is the primary toxicological amatoxin in the "death cap" mushroom Amanita phalloides, and liver is one of the most sensitive organs to ␣-amanitin poisoning (Wills et al 2005;Zhao et al 2006). However, little is known about the underlying molecular pathways involved.…”

Section: ␣-Amanitin Induces P53-mediated Mitochondrial Apoptosis In Lmentioning

confidence: 99%

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Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria

Leu¹,

George²

2007

Genes Dev.

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Liver is generally refractory to apoptosis induced by the p53 tumor suppressor protein, but the molecular basis remains poorly understood. Here we show that p53 transcriptional activation leads to enhanced expression of hepatic IGFBP1 (insulin-like growth factor-binding protein-1). Exhibiting a previously unanticipated role, a portion of intracellular IGFBP1 protein localizes to mitochondria where it binds to the proapoptotic protein BAK and hinders BAK activation and apoptosis induction. Interestingly, in many cells and tissues p53 also has a direct apoptotic function at mitochondria that includes BAK binding and activation. When IGFBP1 is in a complex with BAK, formation of a proapoptotic p53/BAK complex and apoptosis induction are impaired, both in cultured cells and in liver. In contrast, livers of IGFBP1-deficient mice exhibit spontaneous apoptosis that is accompanied by p53 mitochondrial accumulation and evidence of BAK oligomerization. These data support the importance of BAK as a mediator of p53's mitochondrial function. The results also identify IGFBP1 as a negative regulator of the BAK-dependent pathway of apoptosis, whose expression integrates the transcriptional and mitochondrial functions of the p53 tumor suppressor protein.[Keywords: BAK; IGFBP1; mitochondrial apoptosis; p53] Supplemental material is available at http://www.genesdev.org.

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Section: ␣-Amanitin Induces P53-mediated Mitochondrial Apoptosis In Lmentioning

confidence: 67%

Section: ␣-Amanitin Induces P53-mediated Mitochondrial Apoptosis In Lmentioning

confidence: 99%

Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria

Leu¹,

George²

2007

Genes Dev.

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“…They reported a LD 50 of 1000 mg/kg for a single injection or a cumulative dose of 4250 mg/kg divided into 10 injections over 11 days [21]. In a prior study, our lab similarly found evidence of cumulative toxicity and early deaths with a cumulative dose of 1600 mg/kg in mice poisoned with α-amanitin; however, control mice not poisoned with α-amanitin tolerated this dose [8]. We chose more moderate subcutaneous doses of amifostine because of its pharmacokinetic profile and our aim to provide sustained cytoprotection during the acute injury phase without causing inherent toxicity.…”

Section: Discussionmentioning

confidence: 68%

“…Amifostine is approved by the FDA for the prevention of toxicities associated with cisplatin and therapeutic radiation. Amifostine's unique cytoprotective effects have been extensively investigated by cancer treatment researchers, and only recently have its effects been studied as a potential antidote in a toxicologic model [7,8]. WR-1065 is an oxygen and DNA radical scavenger; it interferes with crosslinking of DNA, participates in DNA repair, and induces cellular hypoxia [9,10].…”

Section: Introductionmentioning

confidence: 99%

The effect of amifostine, a cytoprotective agent, on paraquat toxicity in mice

et al. 2007

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Background: Paraquat (PQ) is a highly poisonous herbicide with a variety of toxic effects, most notably pulmonary fibrosis. In alveolar epithelial cells, it is converted to a PQ radical and subsequently generates other reactive species resulting in lipid peroxidation and cell destruction. Amifostine is a thiophosphate prodrug approved by the FDA for the prevention of toxicities associated with cisplatin and therapeutic radiation. When amifostine is converted to an active metabolite (WR-1065), it functions as an oxygen and DNA radical scavenger that has been shown to protect against lipoperoxidation. The aim of this study was to determine whether amifostine improves survival or lung injury resulting from PQ toxicity.Methods: Swiss mice (n = 23 per group) were given an approximate LD 75 dose of PQ intraperitoneal (60 mg/kg). Thirty minutes prior to PQ injection, group 1 was pretreated with 200 mg/kg of amifostine subcutaneously (s.c.). Subsequent doses of amifostine at 75 mg/kg were administered 4 hours after PQ injection, and injections continued every 8 hours for a total of 6 doses (cumulative dose: 575 mg/kg). Four hours after PQ injection, group 2 received 200 mg/kg of amifostine subcutaneously. Subsequent doses of amifostine at 75 mg/kg were administered every 8 hours (cumulative dose: 575 mg/kg). Four hours after PQ injection, group 3 received 100 mg/kg of amifostine subcutaneously. Subsequent doses of amifostine at 30 mg/kg were administered every 8 hours (cumulative dose: 250 mg/kg). Group 4 received equivolume injections of sterile 0.9% saline s.c. at the same time intervals. We removed lungs from all mice for histologic analysis and injury scoring.Results: The number of surviving mice in groups 1, 2, 3, and 4 were 17, 18, 17, and 17 respectively. The Kaplan-Meier with log rank analysis showed no differences in survival. Lung injury scores did not differ between treatment groups and the control group for either dead or surviving mice.Conclusion: Amifostine does not appear to improve survival or lung injury due to PQ toxicity at the doses administered.

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“…Amifostine (Ethyol) a chemo protective agent is a pro drug that converts to its activated form (W-R 1065) by alkaline phosphatase. It has been approved by Food and Drug Administration (FDA) and its cytoprotective effects were examined during a lot of researches on cancer treatment [10]. W-R1065 acts as free radical scavenger and beside cytoprotective effects it can afford protection against toxic effects of ionizing radiation [11] and donates hydrogen ions for DNA repair [12].…”

Section: Introductionmentioning

confidence: 99%

The influence of amifostine administration prior to cyclophosphamide on in vitro maturation of mouse oocytes

Golkar‐Narenji

Barekati

Eimani

et al. 2013

J Assist Reprod Genet

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Purpose The protective effect of amifostine against cyclophosphamide (CP) was evaluated on mouse oocytes. Materials and methods Female mice were divided into four groups as follows: group1: cyclophosphamide (CP) (75 mg/kg, i.p) injection, group2: amifostine (250 mg/kg, i.p) injection, group3: amifostine (250 mg/kg, i.p) administered prior to CP (75 mg/kg, i.p) injection, Control group with injection of saline. About 21 days after injection, in vitro maturation (IVM) of oocytes was recorded. Furthermore the percentage of aneuploid oocytes was determined. Results In the CP group IVM rate was significantly decreased and aneploidy rate was significantly increased when compared to other groups (p<0.05). With the administration of Amifostine prior to CP injection IVM rate was increased and aneploidy rate was decreased. Discussion Depletion in IVM rate with administration of CP is due its adverse effects on oocyte quality. Amifostine administration prior to CP injection appears to modulate deleterious effects of CP on oocytes.

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Use of Amifostine, a Novel Cytoprotective, in α-Amanitin Poisoning

Abstract: No survival benefit was seen with cumulative doses between 250 and 500 mg/kg; however, higher doses may result in subsequent toxicity and decreased survival.

Cited by 6 publications

References 29 publications

Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria

Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria

The effect of amifostine, a cytoprotective agent, on paraquat toxicity in mice

The influence of amifostine administration prior to cyclophosphamide on in vitro maturation of mouse oocytes

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