The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine (Ethyol®)

Capizzi, Robert L.

doi:10.1016/s0959-8049(96)00333-4

Cited by 121 publications

(144 citation statements)

References 53 publications

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“…Amifostine is a phosphorylated aminothiol prodrug that is dephosphorylated by membrane-bound alkaline phosphatase to form the active metabolite WR-1065, a free thiol that exhibits cytoprotective activity after being transported into the cell (van der Vijgh and Peters, 1994;Capizzi, 1999b). Preferential protection of normal cells has been associated with higher activity of membranebound alkaline phosphatase in normal endothelium and normal tissue, compared to neovascular endothelium and tumour tissue (Manheimer and Seligman, 1948;Romanul and Bannister, 1962).…”

Section: Discussionmentioning

confidence: 99%

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

et al. 2003

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To determine the role of p53 protein on the cellular effects of amifostine, we used molecularly engineered HCT116 colon cancer cells in which the p53 gene was inactivated by targeted homologous recombination or p53 protein was degraded by high-level expression of papillomavirus E6 protein. Amifostine induced a G1 arrest and protected against paclitaxel toxicity in p53-proficient but not in p53-deficient cells. In the absence of p53 protein, amifostine enhanced the cytotoxicity of paclitaxel. In addition, treatment of HCT116 cells with amifostine alone resulted in apoptotic cell death. Compared with p53-deficient cells, p53-proficient cells exhibited low-level resistance to amifostine-induced apoptosis. Amifostine induced the expression of p53 protein in p53-proficient cells and the expression of p21 protein in both p53-proficient and -deficient cells. These findings indicate that amifostine-induced G1 arrest and cytoprotection are mediated via a pathway that is dependent on p53 protein and that amifostine-induced expression of p21 protein is not sufficient to sustain a G1 arrest or to mediate cytoprotection. In addition, these findings identify p53 protein as a mechanism of resistance to amifostine-induced apoptosis.

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Section: Discussionmentioning

confidence: 99%

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

et al. 2003

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“…[11][12][13] Amifostine is a pro-drug, the radio protective effect of which is based on the presence of a thiol group in its active metabolite (S-2 [3-aminopropylamino]-ethanethiol). In the plasma, amifostine is rapidly dephosphorylated (by membrane-bound alkaline phosphatase enzymes) and enters the cells as its active form.…”

Section: Discussionmentioning

confidence: 99%

Oxidative study of patients with total body irradiation: effects of amifostine treatment

Facorro

Sarrasague

Torti

et al. 2004

Bone Marrow Transplant

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Summary:In patients undergoing bone marrow transplant (BMT), reactive oxygen species (ROS) are released as a consequence of the events related to the preparative regimen. Total body irradiation (TBI), which is known to generate ROS, is a routine preconditioning procedure prior to BMT. Several studies have demonstrated that amifostine protects normal tissues. In the present report, we investigated the oxidative state of plasma and erythrocytes in 21 patients with hematological malignancies undergoing TBI. The dose fraction was 160 cGy, twice daily (eight sessions). For ROS detection, we used electron spin resonance spectroscopy and spin-trapping technique. In all, 15 patients received amifostine prior to the irradiation and six did not. No free radical signal was detected in the plasma samples spectrum of 15 amifostinetreated patients, and five of six samples of nontreated patients showed ROS signal. Only two of 15 treated patients had mucositis degree higher than 2, whereas five of six nontreated patients suffered this complication. The average hospitalization days in treated and nontreated patients were 23.5 and 29.7, respectively. This work represents an original observation; we found by direct measurements of free radicals that ROS are released during TBI, and confirmed the amifostine radical scavenger activity.

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“…The dose range of 100-200 mg/kg was used in this study because most of the pre-clinical data on cytoprotection of tissues by amifostine in mice and rats are based on doses ranging from 100-400 mg/kg. 15 The dose of 200 mg/kg in rats is equivalent to about 1180 mg/m 2 . 11 The ideal dose of amifostine for different clinical situations remains to be defined, but doses of 740 mg/m 2 or 910 mg/m 2 have been shown to provide cytoprotection in most studies.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of uroprotective efficacy of amifostine against cyclophosphamide induced hemorrhagic cystitis

Srivastava

Nair

Srivastava

et al. 1999

Bone Marrow Transplant

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Summary:The role of amifostine in the prevention of cyclophosphamide-induced hemorrhagic cystitis (HC) was evaluated in the rat model. Urinary bladders from control rats that received no drugs (group I) were compared with those from rats receiving cyclophosphamide alone at a dose of 150 mg/kg (group II), and two other groups receiving amifostine at 100 mg/kg (group III) and 200 mg/kg (group IV), 15 min prior to cyclophosphamide. Bladders were assessed macroscopically and histologically at 24 h and after 7 days. All the animals that received cyclophosphamide alone developed severe HC. On the basis of the scores of macroscopic and histologic changes, animals that received amifostine showed excellent uroprotection. Only 2/6 rats in group III and 1/6 rats in group IV developed mild HC at 24 h. None of the rats in either of these groups showed any evidence of HC at 7 days. It is concluded that amifostine protects the urothelium against cyclophosphamide-induced HC. Keywords: amifostine; cyclophosphamide; hemorrhagic cystitis; prevention Hemorrhagic cystitis (HC) is a potentially life-threatening sequel of therapy with oxazaphosphorine agents (cyclophosphamide, ifosfamide). It tends to occur most frequently as a consequence of using high-dose cyclophosphamide as conditioning therapy for BMT. It has been noted in 40-50% of these patients and contributes to mortality in 2-4%. 1,2 The uro-toxicity of these drugs is related to contact of the lining epithelium with the renally excreted 4-hydroxy metabolites, particularly acrolein. Other factors including viral infections, radiation and drugs such as busulfan may also cause HC in patients undergoing BMT. 2 Since there is no effective treatment for this condition, the emphasis has been on prevention. The most widely employed method for prevention is the combination of 2-mercaptoethane sodium sulfonate (MESNA) and hydration. 3 This thiol molecule has been shown to bind acrolein and reduce its toxicity. In spite of this, up to 18% of patients can develop severe manifestations (grade III to

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The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine (Ethyol®)

Cited by 121 publications

References 53 publications

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

Oxidative study of patients with total body irradiation: effects of amifostine treatment

Evaluation of uroprotective efficacy of amifostine against cyclophosphamide induced hemorrhagic cystitis

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