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1.  Efficacy and tolerability of amifostine in elderly cancer patients 
Background: Amifostine is a cytoprotective agent used to prevent cisplatin nephrotoxicity. It is associated with dose-limiting acute toxicities of emetic symptoms (nausea and vomiting) and transient hypotension.
Objective: The aim of this study was to analyze the efficacy and tolerability of amifostine in elderly cancer patients.
Methods: This 18-month, prospective, comparative study was conducted at the Department of Internal Medicine, Adnan Menderes University Hospital (Aydin, Turkey). Adult (aged 40−<85 years) hospitalized patients with advanced-stage cancer without comorbid diseases were enrolled. Patients were divided into 2 groups: age <70 years (group 1) and ≥70 years (group 2). All patients were treated with amifostine + cisplatin-based chemotherapy (CT). Amifostine 910 mg/m2 (maximum, 1500 mg) was administered as a 15-minute IV infusion. Clinical systolic and diastolic blood pressures (SBP and DBP, respectively) were measured at 0 minute (baseline), at 8 and 15 minutes of amifostine infusion, and at 30 minutes after the start of amifostine infusion. In addition to physical examination, chest radiography, electrocardiography, blood chemistry (including serum electrolytes and renal function tests), complete blood count, and complete urinalyses were performed before each CT administration and at the post-CT day of toxicity assessment.
Results: Thirty-five consecutive patients were enrolled (22 men, 13 women; mean [SD] age, 61 [12] years; group 1, n = 22; group 2, n = 13). Patients received a total of 153 CT cycles (median, 4 cycles/patient; group 1, 96 cycles; group 2, 57 cycles). Amifostine caused significant SBP and DBP reductions at 8 minutes of infusion compared with baseline in groups 1 (both P < 0.001) and 2 (P = 0.002 and P = 0.006, respectively). Overall, 20 patients (57.1%) experienced ≥ 1 symptomatic hypotensive episode; these rates were not significantly different between groups 1 (11 cases, 50.0%) and 2 (9 cases, 69.2%). Amifostine infusion was interrupted a similar number of times (6 times in group 1 and 4 times in group 2 [6.3% and 7.0% of administrations, respectively]) due to hypotension, but could be restarted in all. At 15 minutes, mean SBP and DBP values were not significantly different from baseline in either group. The mean baseline SBP values were similar between groups at baseline, and, overall, the differences in mean SBP and DBP values were not significant between groups at any time point. All other toxicities were comparable, and serum creatinine concentrations did not change significantly from baseline with CT in either group.
Conclusions: In this study of the efficacy and tolerability of amifostine in elderly patients with advanced-stage cancer without comorbid diseases, amifostine was effective in reducing cisplatin-induced nephrotoxicity, with transient systolic and diastolic hypotension being the most prominent adverse effect. All other toxicities were either low grade or preventable. No significant differences in amifostine tolerability or toxicities were observed between the study groups.
PMCID: PMC4052963  PMID: 24936110
amifostine; adverse effects; elderly cancer patients; tolerability; cisplatin; nephrotoxicity
2.  Carboplatin combined with amifostine, a bone marrow protectant, in the treatment of non-small-cell lung cancer: a randomised phase II study. 
British Journal of Cancer  1995;72(6):1551-1555.
Amifostine (WR-2721), a thiol compound, has been shown to protect normal tissue from alkylating agents and cisplatin-induced toxicity without loss of anti-tumour effects. To confirm this result, we conducted a phase II randomised trial to determine if the addition of amifostine reduces the toxicity of carboplatin without loss of anti-tumour activity in patients with inoperable non-small-cell lung cancer (NSCLC). After the first course of carboplatin (600 mg m-2 i.v. infusion), 21 patients were randomised to receive three cycles of carboplatin alone (C arm) or three infusions of amifostine at 910 mg m-2 (CA arm) at 28 day intervals. The amifostine was given 20 min before and at 2 and 4 h after carboplatin. Since the 910 mg m-2 amifostine infusion led to hypotension in six patients, the dosage was reduced by 25%, to 683 mg m-2 t.i.d., in the other four patients. Amifostine was well tolerated at this dose level. Five patients in the CA arm and three in the C arm had their planned treatment discontinued owing to progressive disease (n = 3), amifostine side-effects (hypotension, sneezing and sickness, n = 4), and carboplatin-induced thrombocytopenia (n = 1). Bone marrow and renal function at study entry and after the first course of carboplatin before randomisation were similar in both treatment arms. Twenty courses of carboplatin+amifostine have been compared with 25 courses of carboplatin alone. Although there was no statistically significant difference with respect to haematological values comparing both arms, the median time to platelet recovery (> 100 x 10(9) l-1) (13.5 days vs 21 days; P = 0.04) and the need for hospitalisation for i.v. antibiotic and other supportive treatment tended to be reduced in the CA arm (0/20 vs 6/25 patient courses; P = 0.06). Response rates and median survival (14 vs 9 months) were no different, excluding tumour protection activity by amifostine. These results with a small number of patients suggest that amifostine given with carboplatin may reduce the duration of thrombocytopenia and hospitalisation.
PMCID: PMC2034079  PMID: 8519676
3.  Amifostine does not prevent platinum-induced hearing loss associated with the treatment of children with hepatoblastoma. A report of the Intergroup Hepatoblastoma Study P9645 as a part of the Children's Oncology Group 
Cancer  2009;115(24):5828-5835.
To determine if amifostine is effective in reducing the toxicities associated with the administration of platinum-containing regimens in children with hepatoblastoma (HB).
Patients were enrolled on P9645 beginning in March of 1999. Stage I/II patients received treatment with 4 cycles of cisplatin/5-fluorouracil/vincristine (C5V) +/− amifostine. Patients with Stage III/IV disease were randomized to receive treatment with six cycles of either C5V +/− amifostine or carboplatin alternating with cisplatin (CC) +/− amifostine. Patients randomized to receive amifostine were given a dose of 740 mg/m2 intravenously over 15 minutes prior to each administration of a platinum agent.
Eighty-two patients were considered in a special interim analysis of the incidence of toxicity. The disease outcome for patients receiving amifostine was similar to outcome in patients who did not receive amifostine (p = 0.22). The incidence of significant hearing loss (> 40 dB) was similar for patients treated with or without amifostine: 38% (14/37) vs. 38% (17/45) (p=0.68), respectively. There were no differences in the incidence of renal or bone marrow toxicities evaluated. Patients who received amifostine had a higher incidence of hypocalcemia (5% vs. 0.5%, p=0.00006).
Amifostine in the doses and schedule used in this study failed to significantly reduce the incidence of platinum-induced toxicities in patients with HB.
PMCID: PMC2795100  PMID: 19813275
Hepatoblastoma; Amifostine; Hearing; Ototoxicity
4.  Amifostine reduces the seminiferous epithelium damage in doxorubicin-treated prepubertal rats without improving the fertility status 
Amifostine is an efficient cytoprotector against toxicity caused by some chemotherapeutic drugs. Doxorubicin, a potent anticancer anthracycline, is known to produce spermatogenic damage even in low doses. Although some studies have suggested that amifostine does not confer protection to doxorubicin-induced testicular damage, schedules and age of treatment have different approach depending on the protocol. Thus, we proposed to investigate the potential cytoprotective action of amifostine against the damage provoked by doxorubicin to prepubertal rat testes (30-day-old) by assessing some macro and microscopic morphometric parameters 15, 30 and 60 days after the treatment; for fertility evaluation, quantitative analyses of sperm parameters and reproductive competence in the adult phase were also carried out.
Thirty-day-old male rats were distributed into four groups: Doxorubicin (5 mg/kg), Amifostine (400 mg/kg), Amifostine/Doxorubicin (amifostine 15 minutes before doxorubicin) and Sham Control (0.9% saline solution). "Standard One Way Anova" parametric and "Anova on Ranks" non-parametric tests were applied according to the behavior of the obtained data; significant differences were considered when p < 0.05.
The rats killed 30 and 60 days after doxorubicin treatment showed diminution of seminiferous epithelium height and reduction on the frequency of tubular sections containing at least one type of differentiated spermatogonia; reduction of sperm concentration and motility and an increase of sperm anomalous forms where observed in doxorubicin-treated animals. All these parameters were improved in the Amifostine/Doxorubicin group only when compared to Doxorubicin group. Such reduction, however, still remained below the values obtained from the Sham Control group. Nevertheless, the reproductive competence of doxorubicin-treated rats was not improved by amifostine pre-administration.
These results suggest that amifostine promotes a significant reduction of the doxorubicin long-term side effects on the seminiferous epithelium of prepubertal rats, which is reflected in the epidydimal fluid parameters in the adult phase. However, fertility status results suggest that such protection may not be effective against sperm DNA content damage. Further investigation of sperm DNA integrity must be carried out using amifostine and doxorubicin-treated experimental models.
PMCID: PMC2832784  PMID: 20064221
5.  A randomized trial of amifostine as a cytoprotective agent in patients receiving chemotherapy for small cell lung cancer 
British Journal of Cancer  2001;84(1):19-24.
A randomized trial was conducted to determine whether administration of Amifostine with chemotherapy for small cell lung cancer could decrease the toxicity. 84 patients with small cell lung cancer of favourable prognosis (limited disease, performance status 0–1; limited disease with performance status 2 but normal sodium and alkaline phosphatase, or extensive diseas with performance status 0–1, normal sodium and alkaline phosphatase) received treatment with Ifosfamide 3 g/m2intravenously, Carboplatin (Glomerular filtration rate + 25) ×6 mg intravenously, Etoposide 50 mg orally, twice daily, for 7 days, every 3 weeks. Patients were randomized to receive amifostine 740 mg/m2immediately prior to the intravenous drugs (n = 42) or to receive chemotherapy alone (n = 42). The two groups were similar with respect to baseline prognostic factors. There was no significant difference in the occurrence of grade III or IV neutropenia or thrombocytopenia between the two groups, nor in the response rate or overall survival, for which the median was 11 months in the chemotherapy only group and 14 months in the group treated with amifostine. This study has not shown a protective effect from the use of amifostine with this regimen and there does not appear to be any effect upon the efficacy of treatment. © 2001 Cancer Research Campaign
PMCID: PMC2363622  PMID: 11139307
small cell lung cancer; chemotherapy; myelotoxicity; chemoprotection; amifostine; survival
6.  The protective effect of amifostine on ultraviolet B-exposed xeroderma pigmentosum mice 
ecancermedicalscience  2010;4:176.
Amifostine is a pharmaceutical agent that is used clinically to counteract the side-effects of chemotherapy and radiotherapy. It acts as a free radical scavenger that protects against harmful DNA cross-linking. The purpose of this study was to determine the effect of amifostine on the development of skin cancer in xeroderma pigmentosum (XP) mice exposed to ultraviolet B radiation (UVB).
Twenty-five XP mice were equally divided into five groups. Group 1 (control) received no amifostine and no UVB exposure. Group 2 also received no amifostine, but was exposed to UVB at a dose of 200 mJ/cm2 every other day. The remaining groups were subjected to the same irradiation, but were given amifostine at a dose of 50 mg/kg (group 3), 100 mg/kg (group 4), or 200 mg/kg (group 5) immediately prior to each exposure.
No tumours were seen in the control group. The animals in group 2 (no amifostine) developed squamous cell carcinoma (SCC) at 3.5–4.5 months (mean 3.9 months). Groups 3 and 4 (low- and medium-dose amifostine) developed SCC at 4.0–7.0 months (mean 5.3 months), representing a statistically significant delay in tumour presentation (p = 0.04). An even greater delay was seen in group 5 (high-dose amifostine), which developed SCC at 7.0–9.0 months (mean 8.5 months, p < 0.001 versus groups 3 and 4). Ocular keratitis developed in all animals except the unexposed controls and the high-dose treatment group.
Treatment with amifostine significantly delays the onset of skin cancer and prevents ocular keratitis in UVB-exposed XP mice.
PMCID: PMC3234034  PMID: 22276030
7.  Effect of Amifostine in Head and Neck Cancer Patients Treated with Radiotherapy: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials 
PLoS ONE  2014;9(5):e95968.
Amifostine is the most clinical used chemical radioprotector, but its effect in patients treated with radiation is not consistent.
By searching Medline, CENTRAL, EMBASE, ASCO, ESMO, and CNKI databases, the published randomized controlled trials (RCTs) about the efficacy of amifostine in HNSCC patients treated with radiotherapy were collected. The pooled efficacy and side effects of this drug were calculated by RevMan software.
Seventeen trials including a total of 1167 patients (604 and 563 each arm) were analyzed in the meta-analysis. The pooled data showed that the use of amifostine significantly reduce the risk of developing Grade3–4 mucositis (relative risk [RR],0.72; 95% confidence interval [CI],0.54–0.95; p<0.00001), Grade 2–4 acute xerostomia (RR,0.70; 95%CI,0.52–0.96; p = 0.02), or late xerostomia (RR,0.60; 95%CI,0.49–0.74; p<0.00001) and Grade 3–4 dysphagia (RR,0.39; 95%CI,0.17–0.92; p = 0.03). However, subgroup analysis demonstrated that no statistically significant reduction of Grade3–4 mucositis (RR,0.97; 95% CI,0.74–1.26; p = 0.80), Grade 2–4 acute xerostomia (RR,0.35; 95%CI,0.02–5.44; p = 0.45), or late xerostomia (RR,0.40; 95%CI,0.13–1.24; p = 0.11) and Grade 3–4 dysphagia (RR,0.23; 95%CI,0.01–4.78; p = 0.35) was observed in patients treated with concomitant chemoradiotherapy. Compared with placebo or observation, amifostine does not show tumor protective effect in complete response (RR,1.02; 95%CI,0.89–1.17; p = 0.76) and partial response (RR,0.90; 95%CI, 0.56–1.44; p = 0.66). For the hematologic side effect, no statistical difference of Grade 3–4 leucopenia (RR,0.60; 95%CI,0.35–1.05; p = 0.07), anemia (RR,0.80; 95%CI, 0.42–1.53; p = 0.50) and thrombocytopenia (RR,0.43; 95%CI,0.16–1.15; p = 0.09) were found between amifostine and control groups. The most common amifostine related side effects were nausea, emesis, hypotension and allergic with an average incidence rate (Grade 3–4) of 5%, 6%, 4% and 4% respectively.
This systematic review showed that amifostine significantly reduce the serious mucositis, acute/late xerastomia and dysphagia without protection of the tumor in HNSCC patients treated with radiotherapy. And the toxicities of amifostine were generally acceptable.
PMCID: PMC4008569  PMID: 24788761
8.  Clinical Pharmacokinetics of Amifostine and WR1065 in Pediatric Patients with Medulloblastoma 
We evaluated the pharmacokinetics of amifostine and WR1065 in pediatric patients with newly diagnosed medulloblastoma, to assess the influence of patient covariates, including demographics, clinical characteristics, and genetic polymorphisms, on amifostine and WR1065 pharmacokinetic parameters.
Experimental design
We assessed the pharmacokinetics of amifostine and WR1065 in 33 children who received amifostine (1 min infusion, 600 mg/m2) just prior to the start of and 3 hours into a 6-hour cisplatin infusion. Serial blood samples were collected after doses 1 (0 hr) and 2 (3 hr) of course 1. Amifostine and WR1065 were quantitated by HPLC with electrochemical detection. A pharmacokinetic model was simultaneously fit to amifostine and WR1065 plasma or whole blood concentration-versus-time data. The influence of demographic, biochemical, and pharmacogenetic covariates on amifostine and WR1065 disposition was evaluated.
Body surface area was the primary size-based covariate for amifostine pharmacokinetics explaining 53% and 56% of interindividual variability in plasma and whole blood amifostine clearance, respectively. The population predicted values for amifostine clearance, volume, and apparent WR1065 clearance from the plasma data were: 107 L/hr/m2, 5.53 L/m2, and 30.6 L/hr/m2. The population predicted values for amifostine clearance, volume, and apparent WR1065 clearance from whole blood data were 136 L/hr/m2, 7.23 L/m2, and 12.5 L/hr/m2.
These results support using body surface area for calculating doses of amifostine in children. Similar to data in adults, amifostine and WR1065 are rapidly cleared from plasma and whole blood in children.
PMCID: PMC2818675  PMID: 20103669
Pharmacokinetics; pediatrics; amifostine; pharmacogenetics; WR1065
9.  The addition of amifostine to carboplatin and paclitaxel based chemoradiation in locally advanced non-small cell lung cancer: long-term follow-up of Radiation Therapy Oncology Group (RTOG) randomized trial 9801 
We report the long-term results of RTOG 9801, a randomized trial investigating the ability of amifostine, a radioprotector, to reduce chemoradiation-induced esophagitis.
Patients with stage II and IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m2 intravenously (IV) and carboplatin area under the curve (AUC) 6 both days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m2) and carboplatin (AUC 2), with hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy BID). Patients were randomly assigned to amifostine (AM) 500 mg IV four times per week or no-AM during chemoradiotherapy. Stratification factors included age (< 70 v ≥ 70 years), stage and performance status.
243 patients (pts) were enrolled; 120 received AM, 123 received no-AM. Two pts on each arm were found ineligible. Overall, 85% of patients were ≤70 years; 75% had a KPS ≥90. 34% had squamous histology. With median follow-up of 96.3 months (for patients still alive), overall survival was identical (Hazard ratio 1.03 (0.79–1.34), NS): five-year survival 17% in both arms. The incidence of late grade 3–5 toxicities was 16% in the AM arm and 19% in the control arm (Hazard ratio 1.24 (0.66–2.32), NS). There was no significant difference between the arms regarding overall survival, disease-free survival or long-term toxicity.
The chemoradiation regimen of carboplatin and paclitaxel produced long-term results in the multi-institutional setting comparable to other regimens. Amifostine did not appear to compromise survival. Better data is required regarding the comparative long-term toxicity of different chemoradiation regimens. NCT00003313.
PMCID: PMC3646966  PMID: 23477890
NSCLC; non-small cell lung cancer; chemoradiation; carboplatin; paclitaxel; amifostine
10.  Amifostine enhances the antioxidant and hepatoprotective effects of UW and HTK preservation solutions 
World Journal of Gastroenterology : WJG  2014;20(34):12292-12300.
AIM: To investigate whether amifostine contributes to the antioxidant and cytoprotective effects of histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions.
METHODS: Forty-eight Sprague Dawley male rats were equally divided into six groups: (1) ringer Lactate (RL) group; (2) RL + amifostine (RL + A) group; (3) HTK group; (4) HTK + A group; (5) UW group; and (6) UW + A group. Rats in the RL + A, HTK + A and UW + A groups were administered amifostine intraperitoneally at a dose of 200 mg/kg prior to laparotomy. The RL group was perfused with RL into the portal vein. The RL + A group were perfused with RL into the portal vein after amifostine administration. The HTK group received an HTK perfusion while the HTK + A group received an HTK perfusion after administration of amifostine. The UW group received a perfusion of UW, while the UW + A group received a UW perfusion after amifostine administration. Liver biopsy was performed to investigate histopathological, immunochemical [transferase mediated dUTP nick end labeling (TUNEL), inducible nitric oxide syntetase (iNOS)] and ultrastructural alterations. Biochemical alterations were determined by examining levels of alanine aminotransferase, alkaline phosphatase and nitric oxide in the perfusion fluid.
RESULTS: Pathological sinusoidal dilatation and centrilobular hydropic alteration were significantly lower in the groups that received amifostine prior to preservation solution perfusion. Although the best results were obtained in the UW + A group, we did not observe a statistically significant difference between the UW + A and HTK + A groups. iNOS grades were significantly lower in the amifostine groups 12 h after treatment. When the amifostine groups were compared against each other, the iNOS grades obtained from the UW + A and HTK + A groups were similar while the RL + A group had a much poorer score. TUNEL assays demonstrated a lower apoptosis ratio in the amifostine groups than in the non-amifostine groups 12 h after treatment. No statistically significant difference was observed between the UW + A and HTK + A groups for apoptosis. Cellular ultrastructure was best preserved in the UW + A and HTK + A groups.
CONCLUSION: Here, we show that preoperative administration of a single dose of amifostine is sufficient to minimize the preservation damage in hepatic cells.
PMCID: PMC4161815  PMID: 25232264
Liver; Transplantation; Preservation solutions; Histidine-tryptophan-ketoglutarate; University of Wisconsin; Antioxidant; Amifostine
11.  Influence of single and multiple doses of amifostine on the efficacy and the pharmacokinetics of carboplatin in mice. 
British Journal of Cancer  1997;75(10):1439-1446.
We have previously reported that amifostine potentiates the anti-tumour activity of carboplatin in mice. The present study was carried out in well-established human ovarian cancer xenografts OVCAR-3, A2780 and FMa grown subcutaneously in the nude mouse. It was found that a single dose of amifostine resulted in a higher increase in the anti-tumour activity of carboplatin than three doses of amifostine. A single dose of amifostine increased the AUC (area under the curve) values of total platinum in plasma ultrafiltrate (30.1 vs 18.2 microM x h), liver (307.7 vs 236.4 nmol g(-1) x h), kidney (500.8 vs 368.3 nmol g(-1) x h) and OVCAR-3 tumour tissue (184.0 vs 146.8 nmol g(-1) x h). Despite this increase in total platinum, a decrease in platinum (Pt)-DNA adduct levels was observed in liver, kidney and bone marrow, which was significant in liver. In tumour tissue an insignificant increase in Pt-DNA adduct levels, specifically the Pt-GG adduct, was observed after treatment with a single dose of amifostine, which may explain the increase in anti-tumour activity. The increase in the AUC of total platinum was probably caused by a reduction in body temperature, which was most severe after three doses of amifostine. The extreme hypothermia may be the reason that three doses of amifostine resulted in less potentiation of the efficacy of carboplatin.
PMCID: PMC2223489  PMID: 9166935
12.  Induction of cellular antioxidant defense by amifostine improves ventilator induced lung injury 
Critical care medicine  2011;39(12):2711-2721.
To test the hypothesis that preconditioning animals with amifostine improves ventilator induced lung injury via induction of antioxidant defense enzymes. Mechanical ventilation at high tidal volume (HTV) induces reactive oxygen species (ROS) production and oxidative stress in the lung, which plays a major role in the pathogenesis of VILI. Amifostine attenuates oxidative stress and improves LPS-induced lung injury by acting as a direct scavenger of reactive oxygen and nitrogen species. This study tested effects of chronic amifostine administration on parameters of oxidative stress, lung barrier function and inflammation associated with ventilator induced lung injury.
Randomized and controlled laboratory investigation in mice and cell culture.
University laboratory.
C57BL/6J mice.
Mice received once-daily dosing with amifostine (10-100 mg/kg, intraperitoneal injection) 3 days consecutively prior to HTV ventilation (30 ml/kg, 4 hrs) at day 4. Pulmonary endothelial cell (EC) cultures were exposed to pathological cyclic stretching (18% equibiaxial stretch) and thrombin in a previously-verified two-hit model of in vitro VILI.
Measurements and Main Results
Three-day amifostine preconditioning prior to HTV: 1) attenuated HTV-induced protein and cell accumulation in the alveolar space judged by BALF analysis; 2) decreased Evans Blue dye extravasation into the lung parenchyma; 3) decreased biochemical parameters of HTV-induced tissue oxidative stress; and 4) inhibited HTV-induced activation of redox-sensitive stress kinases and NF-κB inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 (SOD2) expression and increased SOD and catalase enzymatic activities in the animal and endothelial cell culture models of VILI.
Amifostine preconditioning activates lung tissue antioxidant cell defense mechanisms and may be a promising strategy for alleviation of VILI in critically ill patients subjected to extended mechanical ventilation.
PMCID: PMC3657468  PMID: 21765345
Ventilator-induced lung injury; Amifostine; Endothelium; Reactive oxygen species; Superoxide dismutase 2
13.  Antiretroviral activity of the aminothiol WR1065 against Human Immunodeficiency virus (HIV-1) in vitro and Simian Immunodeficiency virus (SIV) ex vivo 
WR1065 is the free-thiol metabolite of the cytoprotective aminothiol amifostine, which is used clinically at very high doses to protect patients against toxicity induced by radiation and chemotherapy. In an earlier study we briefly reported that the aminothiol WR1065 also inhibits HIV-1 replication in phytohemagglutinin (PHA)-stimulated human T-cell blasts (TCBs) infected in culture for 2 hr before WR1065 exposure. In this study we expanded the original observations to define the dose-response curve for that inhibition, and address the question of additive effects for the combination of WR1065 plus Zidovudine (AZT). Here we also explored the effect of WR1065 on SIV by examining TCBs taken from macaques with well-established infections several months with SIV.
TCBs from healthy human donors were infected for 2 hr with HIV-1, and viral replication (p24) was measured after 72 hr of incubation with or without WR1065, AZT, or both drugs. HIV-1 replication, in HIV-1-infected human TCBs, was inhibited by 50% at 13 μM WR1065, a dose at which 80% of the cells were viable. Cell cycle parameters were the same or equivalent at 0, 9.5 and 18.7 μM WR1065, showing no drug-related toxicity. Combination of AZT with WR1065 showed that AZT retained antiretroviral potency in the presence of WR1065. Cultured CD8+ T cell-depleted PHA-stimulated TCBs from Macaca mulatta monkeys chronically infected with SIV were incubated 17 days with WR1065, and viral replication (p27) and cell viability were determined. Complete inhibition (100%) of SIV replication (p27) was observed when TCBs from 3 monkeys were incubated for 17 days with 18.7 μM WR1065. A lower dose, 9.5 μM WR1065, completely inhibited SIV replication in 2 of the 3 monkeys, but cells from the third macaque, with the highest viral titer, only responded at the high WR1065 dose.
The study demonstrates that WR1065 and the parent drug amifostine, the FDA-approved drug Ethyol, have antiretroviral activity. WR1065 was active against both an acute infection of HIV-1 and a chronic infection of SIV. The data suggest that the non-toxic drug amifostine may be a useful antiretroviral agent given either alone or in combination with other drugs as adjuvant therapy.
PMCID: PMC2777914  PMID: 19895691
14.  Amifostine Protects Against Cisplatin-Induced Ototoxicity in Children with Average-Risk Medulloblastoma 
To determine the role of amifostine as a protectant against cisplatin-induced ototoxicity in patients with average risk (AR) medulloblastoma treated with craniospinal radiotherapy and 4 cycles of cisplatin-based dose-intense chemotherapy and stem cell rescue.
Patients and Methods
The primary objective was to determine whether, in patients with AR medulloblastoma (n=62), amifostine would decrease the need for hearing aids (defined as ≥ grade 3 ototoxicity in one ear) compared to a control group (n=35), one year from initiating treatment. (Figure 1) Ninety-seven patients received CSI (23.4 Gy) followed by 55.8 Gy to the primary tumor bed, using 3-D conformal technique and 4 cycles of high-dose cyclophosphamide (4000 mg/m2 per cycle), cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5 mg/m2 doses per cycle) and stem cell rescue. When used, amifostine (600 mg/m2 per dose) was given as a bolus immediately prior to and 3 hours into the cisplatin infusion.
The median age of the 97 patients was 8.7 years (range, 3.2–20.2 years). The study and control groups were similar in age and sex distribution. Amifostine was well-tolerated. One year after treatment initiation, 13 (37.1%) of the control-group versus 9 (14.5%; p=0.005 Chi-Square one-sided test) of the amifostine-treated patients had ≥ grade 3 ototoxicity, requiring hearing aid in at least one ear.
Amifostine administered prior to and during the cisplatin infusion can significantly reduce the risk of severe ototoxicity in patients with AR medulloblastoma receiving dose-intense chemotherapy.
PMCID: PMC2504739  PMID: 18669462
amifostine; ototoxicity; cisplatin
15.  Assessment of the effect of local application of amifostine on acute radiation-induced oral mucositis in guinea pigs 
Journal of Radiation Research  2014;55(5):847-854.
The aim of present study was to assess the radioprotective effects of the local application of amifostine to treat acute buccal mucositis in guinea pigs. A total of 32 guinea pigs were randomized into four groups: (Group A) topically administered 50 mg of amifostine plus radiotherapy (RT); (Group B) 100 mg amifostine plus RT; (Group C) normal saline plus RT; and (Group D) normal saline plus sham RT. The opportunity for administration was 15 min before irradiation. When administered, the cotton pieces that had been soaked with 0.5 ml amifostine solution or saline were applied gently on the buccal mucosa of each guinea pig for 30 min. The animals in Groups A, B and C were irradiated individually with a single dose of 30 Gy to the bilateral buccal mucosa. Eight days after irradiation, the animals were scored macroscopically; they were then euthanized, and the buccal mucosal tissues were processed for hematoxylin–eosin staining and ICAM-1 immunohistochemical analysis. In Groups A and B, the mean macroscopic scores were 2.9 ± 0.6 and 2.4 ± 1.1, respectively. There was no significant difference between the two groups (P > 0.05). However, when they were separately compared with Group C (4.4 ± 0.7), a noticeable difference was obtained (P < 0.05). No mucositis was observed in Group D. Comparisons of the expression of ICAM-1 were in agreement with the macroscopic data. Histologically, superficial erosion, exudate and ulcer formation were all observed in the RT groups; only the severity and extent were different. The microscopic observations in the amifostine-treated groups were better than in Group C. The results demonstrated that topical administration of amifostine to the oral mucosa is effective treatment of acute radiation-induced mucositis.
PMCID: PMC4202282  PMID: 24706999
amifostine; local application; intercellular adhesion molecule-1 (ICAM-1); oral mucositis; guinea pig
16.  Use of amifostine in the treatment of recurrent solid tumours in children 
Hippokratia  2007;11(1):25-29.
Preclinical and clinical evaluation of amifostine (AMI) administration in conjunction with systemic chemotherapy supports its role as a cytoprotective agent of normal tissues without loss of impairing the antitumour effectiveness of chemotherapeutic agents. Since only a limited number of clinical studies has been performed using AMI in paediatric pts with malignancies we investigated the protective effect of AMI against carboplatin-induced myelotoxicity and nephrotoxicity in a paediatric group of patients. Material and results: AMI was administered in 18/28 paediatric patients with reccurent solid tumours along with ICE (ifosfamide, carboplatin, etoposide) chemotherapy. A significant (p<0.05) decrease in GFR was observed in the control group whereas it was maintained at pre – treatment levels in the AMI-treated group. Leukopenia and neutropenia were significantly (p<0.05) less in AMI-group. No protective effect of AMI was shown concerning thrombocytopenia. Conclusions: AMI was generally well tolerated at the dose of 740 mg/m². Side effects including nausea, vomiting, hypotension, flushing and rigors were moderate and reversible and the interruption of infusion was never required.
PMCID: PMC2464265  PMID: 19582173
recurrent solid tumours; paediatric neoplasms; chemotherapy; cytoprotection; amifostine
17.  Randomized phase II exploratory study of prophylactic amifostine in cancer patients who receive radical radiotherapy to the pelvis 
This study aimed to investigate the efficacy of prophylactic amifostine in reducing the risk of severe radiation colitis in cancer patients receiving radical radiotherapy to the pelvis.
Patients with pelvic tumours referred for radical radiotherapy who consented participation in this trial, were randomly assigned to receive daily amifostine (A) (subcutaneously, 500 mg flat dose) before radiotherapy or radiotherapy alone (R). Sigmoidoscopy and blinded biopsies were scheduled to conduct prior to initiation and following completion of radiotherapy and again 6 to 9 months later. Radiation colitis was assessed by clinical, endoscopic and histolopathological criteria.
A total 44 patients were enrolled in this trial, the majority with rectal (20 patients) and cervical cancer (12 patients) and were assigned 23 in R arm and 21 in the A arm. In total 119 sigmoidoscopies were performed and 18 patients (18/44, 40.9%) were diagnosed with radiation colitis (15 grade 1 and 2, and 3 grade 3 and 4). Of them, 6 patients belonged to the A group (6/21, 28.6%) and 12 to the R group (12/23, 52.2%). Acute and grade IV radiation colitis was only developed in four patients (17.4%) in the R group. Amifostine side effects were mild. Amifostine treated patients were less likely to develop histologically detectable mucosal lesions, which indicate protection from acute mucosal injury.
Amifostine given subcutaneously can lower the risk of acute severe radiation colitis in patients who receive radical radiotherapy to pelvic tumors.
PMCID: PMC2903531  PMID: 20537164
18.  Concurrent administration of Docetaxel and Stealth® liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection 
British Journal of Cancer  2002;87(4):385-392.
The substantial augmentation of the radiation sequelae during chemo–radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo–radiotherapy scheme with Stealth® liposomal doxorubicin (Caelyx®) and Docetaxel (Taxotere®) in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere® was 20 mg m−2 week and of Caelyx® was 15 mg m−2 every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere®/Caelyx® was, thereafter, increased to 20/25 (five patients) and 30/25 mg m−2 (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The ‘in-field’ radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere®/Caelyx® chemo–radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the ‘in-field’ toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer.
British Journal of Cancer (2002) 87, 385–392. doi:10.1038/sj.bjc.6600486
© 2002 Cancer Research UK
PMCID: PMC2376133  PMID: 12177774
radiotherapy; amifostine; stealth liposomal doxorubicin; docetaxel; non-small cell lung cancer
19.  Radioprotection of hematopoietic progenitors by low dose amifostine prophylaxis 
Amifostine is a highly efficacious cytoprotectant when administered in vivo at high doses. However, at elevated doses, drug toxicity manifests for general, non-clinical radioprotective purposes. Various strategies have been developed to avoid toxic side-effects: The simplest is reducing the dose. In terms of protecting hematopoietic tissues, where does this effective, non-toxic minimum dose lie?
Material and methods
C3H/HEN mice were administered varying doses of amifostine (25–100 mg/kg) 30 min prior to cobalt-60 irradiation and euthanized between 4–14 days for blood and bone marrow collection and analyses.
Under steady-state, amifostine had little effect on bipotential and multi-potential marrow progenitors but marginally suppressed a more primitive, lineage negative progenitor subpopulation. In irradiated animals, prophylactic drug doses greater than 50 mg/kg resulted in significant regeneration of bipotential progenitors, moderate regeneration of multipotential progenitors, but no significant and consistent regeneration of more primitive progenitors. The low amifostine dose (25 mg/kg) failed to elicit consistent and positive, radioprotective actions on any of the progenitor subtypes.
Radioprotective doses for amifostine appear to lie between 25 and 50 mg/kg. Mature, lineage-restricted progenitors appear to be more responsive to the protective effects of low doses of amifostine than the more primitive, multipotential progenitors.
PMCID: PMC4133974  PMID: 24597748
Amifostine; bone marrow; hematopoietic progenitors; radiation; radioprotectants; WR2721
20.  Radioiodine-induced kidney damage and protective effect of amifostine: An experimental study 
Hippokratia  2012;16(1):40-45.
Background: Ablative radioiodine-131 (131I) therapy is used in the standart treatment procedure of thyroid carcinoma and procedures using 131I represent the majority of Nuclear Medicine therapeutic procedures. The principal route of 131I excretion after the administration of 131I is the urine. Amifostine is an organic thiophosphate ester prodrug and the kidney concentrations of the active metabolite WR-1065 are about 100 times higher than tumour concentrations. To our knowledge, there is no published data in literature presenting acute effect of radioiodine on renal tissue during high dose I-131 radioiodine treatment (RIT). Additionally, it is not known whether amifostine takes role in this process.
Materials and Methods: In this study, 50 healthy female Wistar albino rats, weighing 200–250 g and averaging 16 weeks old were utilised. The rats were randomly divided into ten groups. 1- Sham group (n=5), 2- Amifostine group (n=5): rats pretreated with 1 cc amifostine (200 mg/kg) by intraperitoneal injection, 3- Radioactive iodine first day group (RI-1) (n=5): rats treated with 1 cc oral 185 MBq radioactive iodine-131 and sacrification performed after 1st day, 4- Amifostine + Radioactive iodine first day group (A+RI-1) (n=5): rats pretreated with amifostine (200 mg/kg) by intraperitoneal injection and rats treated with 5mCi radioactive iodine-131 and sacrification performed after 1st day. 5- Radioactive iodine third day group (RI-3) (n=5), 6- Amifostine + Radioactive iodine third day group (A+RI-3) (n=5), 7- Radioactive iodine fifth day group (RI-5) (n=5), 8- Amifostine + Radioactive iodine fifth day group (A+RI-5) (n=5), 9- Radioactive iodine seventh day group (RI-7) (n=5) and 10- Amifostine + Radioactive iodine seventh day group (A+RI-7) (n=5). The renal cast formation and tubular damage are evaluated by a pathologist in a blinded manner.
Results: Ablative radioiodine-131 therapy induced renal tubular damage was significantly higher in the radioactive iodine fifth day group (RI-5) when compared with the Sham group (p=0.01) and Amifostine group (p=0.01).
Conclusions: A marked ablative radioiodine-131 induced renal toxicity was seen at fifth day of the therapy after a single RIT application and the main histopathological change was tubular damage. Amifostine have protective effects against ablative radioiodine-131 therapy and this effect is significant at fifth day of the therapy.
PMCID: PMC3738391  PMID: 23930056
amifostine; radioiodine therapy; renal toxicity
21.  L-Carnitine Protection Against Cisplatin Nephrotoxicity In Rats: Comparison with Amifostin Using Quantitative Renal Tc 99m DMSA Uptake 
Objective: In this study, we aimed to investigate the cytoprotective effect of L-carnitine against cisplatin-induced nephrotoxicity and to compare its efficacy with that of amifostin by quantitative renal Tc 99m DMSA uptake.
Material and Methods: Male Wistar rats were randomly divided into six groups of six animals each. 1) Control (saline; 5 ml/kg intraperitoneally); 2) L-carnitine (CAR; 300 mg/kg intraperitoneally); 3) Amifostine (AMI; 200 mg /kg intraperitoneally); 4) Cisplatin (CIS;7 mg/kg intraperitoneally); 5) Cisplatin plus L-carnitine (CIS + CAR); 6) Cisplatin plus amifostine (CIS + AMI). L-carnitine and amifostine were injected 30 minutes before cisplatin in Group 5 and 6. Tc 99m DMSA, 7.4 MBq/0.2 ml, was injected through the tail vein 72 hours after the drug administration. Rats were killed and kidneys removed by dissection 2 hours after the injection of the radiopharmaceutical. The percentage of the injected dose per gram of kidney tissue (%ID/g) was calculated. Renal function was monitored by measuring BUN and plasma levels of creatinine. Lipid peroxidation and glutathione content were determined by measuring malondialdehyde (MDA) and reduced glutathione (GSH) in kidney tissue homogenates.
Results: Tc 99m DMSA uptake per gram tissue of the kidney as %ID/g was 29.54±4.72, 29.86 ± 7.47 and 26.37 ± 4.54 in the control, CAR and AMI groups respectively. %ID/g was the lowest of all the groups, 11.60±3.59 (p<0.01), in the cisplatin group. Carnitine or amifostine administration 30 minutes before cisplatin injection resulted a significant increase in %ID/g, 21.28±7.73 and 18.97±3.24 respectively, compared to those of cisplatin-treated rats (p<0.002). A marked increase in plasma BUN and creatinine indicating nephrotoxicity and acute renal failure was observed in the cisplatin-treated group. MDA and GSH levels were concordant with cisplatin-induced oxidative stress in the kidney tissue.
Conclusion: The results showed that L-carnitine significantly attenuates the cisplatin-induced nephrotoxicity as amifostin.
Conflict of interest:None declared.
PMCID: PMC3590933  PMID: 23486728
Spermatic cord torsion; radionuclide imaging; cryptorchidism; inguinal hernia
22.  Prophylactic Amifostine Preserves the Biomechanical Properties of Irradiated Bone in the Murine Mandible 
Plastic and reconstructive surgery  2014;133(3):314e-321e.
The authors have previously demonstrated that amifostine prophylaxis mitigates the pernicious effects of radiation in settings of fracture repair and distraction osteogenesis. Expanding on these studies, the authors examined the biomechanical properties of uninjured bone exposed to both radiation and amifostine. The authors hypothesize that radiation will degrade the biomechanical properties of native bone, and further hypothesize that prophylactic amifostine will preserve biomechanical properties to levels of normal bone and protect against radiation-induced morbidities.
Rats were randomized into control, irradiated, and amifostine pretreatment plus radiation (amifostine-pretreated) groups. Irradiated animals received a fractionated dosing schedule of 35 Gy, with amifostine-pretreated animals receiving amifostine before irradiation. Hemimandibles were harvested at 8 and 18 weeks for biomechanical testing and micro–computed tomographic analysis.
At 8 weeks, irradiated specimens displayed elevations above controls for all biomechanical properties. At 18 weeks, the biomechanical properties of irradiated specimens degraded in comparison with controls; at both time points, amifostine-pretreated specimens were maintained at levels comparable to controls. There was a significant decrease in tissue mineral density from 8- to 18-week irradiated specimens, whereas no such change existed for control and amifostine-pretreated specimens.
The authors’ findings demonstrate paradoxical and transient elevations in the initial biomechanical properties of irradiated specimens that were not sustained through the later study time point. Amifostine pretreatment, however, provided uninterrupted preservation of the biomechanical properties of normal, native bone at both time points. This supports the contention that amifostine is capable of providing continuous protection to bone against the untoward effects of radiation therapy.
PMCID: PMC4163550  PMID: 24572876
23.  Results of a planned interim toxicity analysis with trimodality therapy, including carboplatin AUC = 4, paclitaxel, 5-fluorouracil, amifostine, and radiation for locally advanced esophageal cancer: preliminary analyses and treatment recommendations from the North Central Cancer Treatment Group 
An aggressive trimodality approach from the Minnie Pearl Cancer Research Network [carboplatin AUC = 6, days 1 and 22; 5-fluorouracil 225 mg/m2 continuous infusion, days 1–42, paclitaxel 200 mg/m2, days 1 and 22; 45 Gy] has resulted in remarkable pathologic response rates but notable toxicity. This trial was designed to mitigate this toxicity by starting with a lower carboplatin dose, AUC = 4, and by adding subcutaneous amifostine.
This phase II trial included patients with locally advanced, potentially resectable esophageal cancer. All were to receive the above regimen with modifications of carboplatin AUC = 4 and amifostine 500 mg subcutaneously before radiation. All were then to undergo an esophagectomy. A planned interim toxicity analysis after the first 10 patients was to determine whether the carboplatin dose should escalate to AUC = 6.
Ten patients were enrolled, and all required dose reductions/omissions during neoadjuvant therapy. One patient died from paclitaxel anaphylaxis. Six patients manifested a complete pathologic response.
With this regimen, carboplatin AUC = 4 for patients with locally advanced esophageal cancer is appropriate.
PMCID: PMC529465  PMID: 15533252
24.  Pre-Treatment with Amifostine Protects against Cyclophosphamide-Induced Disruption of Taste in Mice 
PLoS ONE  2013;8(4):e61607.
Cyclophosphamide (CYP), a commonly prescribed chemotherapy drug, has multiple adverse side effects including alteration of taste. The effects on taste are a cause of concern for patients as changes in taste are often associated with loss of appetite, malnutrition, poor recovery and reduced quality of life. Amifostine is a cytoprotective agent that was previously shown to be effective in preventing chemotherapy-induced mucositis and nephrotoxicity. Here we determined its ability to protect against chemotherapy-induced damage to taste buds using a mouse model of CYP injury. We conducted detection threshold tests to measure changes in sucrose taste sensitivity and found that administration of amifostine 30 mins prior to CYP injection protected against CYP-induced loss in taste sensitivity. Morphological studies showed that pre-treatment with amifostine prevented CYP-induced reduction in the number of fungiform taste papillae and increased the number of taste buds. Immunohistochemical assays for markers of the cell cycle showed that amifostine administration prevented CYP-induced inhibition of cell proliferation and also protected against loss of mature taste cells after CYP exposure. Our results indicate that treatment of cancer patients with amifostine prior to chemotherapy may improve their sensitivity for taste stimuli and protect the taste system from the detrimental effects of chemotherapy.
PMCID: PMC3634019  PMID: 23626702
25.  Interventions for preventing neuropathy caused by cisplatin and related compounds 
Cisplatin and several related antineoplastic agents used to treat many types of solid tumors are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought.
To examine the efficacy of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related agents.
Search methods
We searched the Cochrane Neuromuscular Disease Group Specialized Register (25 August 2010), the Cochrane Central Register of Controlled Trials (Issue 3, 2010 in The Cochrane Library), MEDLINE (January 1966 to August 2010), EMBASE (January 1980 to August 2010), LILACS (January 1982 to August 2010), CINAHL (January 1982 to August 2010) for randomized trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related agents among human patients.
Selection criteria
Quasi-randomized or randomized controlled trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant (acetylcysteine, amifostine, ACTH, BNP7787, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, or vitamin E) and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary).
Data collection and analysis
We identified 16 randomized trials involving five possible chemoprotective agents in the initial 2006 review. Each study was reviewed by two authors who extracted the data and reached consensus. The 2010 update identified 11 additional randomized trials consisting of nine possible chemoprotective agents, including three treatments (acetylcysteine, calcium and magnesium, and oxcarbazepine) not among those described in the 2006 review. The included trials in the updated review involved eight unrelated treatments and included many disparate measures of neuropathy, resulting in insufficient data for any one measure to combine the results in most instances.
Main results
One of four eligible amifostine trials (541 total participants in all four trials) used quantitative sensory testing and demonstrated a favorable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Of the six eligible glutathione trials (354 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing reported disparate results; meta-analyses of three trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. The single eligible trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), calcium and magnesium (33 participants), and oxcarbazepine (32 participants) and the two eligible trials involving vitamin E (57 participants) did not perform quantitative sensory testing. In all, data from 1,537 participants were included.
Authors' conclusions
At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxycarbazepine, or Vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients.
PMCID: PMC3715044  PMID: 21328275
Antineoplastic Agents [*adverse effects]; Cisplatin [*adverse effects analogs & derivatives]; Neuroprotective Agents [*therapeutic use]; Peptide Fragments [therapeutic use]; Peripheral Nervous System Diseases [chemically induced; *prevention & control]; Humans

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