Protective Effect Of Amifostine Research Articles

Protective Effect of Amifostine against Etoposide-Induced Genotoxicity Evaluated By the Comet Assays

Protective Effect of Amifostine against Etoposide-Induced Genotoxicity Evaluated By the Comet Assays

Protective effects of amifostine, curcumin, and melatonin against cisplatin-induced acute kidney injury

Despite the enormous advances made in the field of oncology, no solution to the side effect of nephrotoxicity caused by cisplatin used as an antineoplastic agent for approximately 40years has yet been discovered. This study investigated the effects of cisplatin on the kidney, the damage mechanism involved, and the potential capacity of agents such as amifostine, curcumin, and melatonin to elicit a future therapeutic protocol in cisplatin-induced nephrotoxicity at the ultrastructural and molecular levels. Our study consisted of five groups: control (saline solution only; group 1), cisplatin (cisplatin only; group 2), cisplatin + amifostine (group 3), cisplatin + curcumin (group 4), and cisplatin + melatonin (group 5). Rats in all groups except the control group were administered a single intraperitoneal dose of 7.5mg/kg cisplatin. All animals were sacrificed under anesthesia on the sixth day after cisplatin administration. Cisplatin increased serum urea and serum creatinine levels and caused an increase in tubular necrosis scores (TNS), HPS, NF-κB/p65, 8-OHdG, and caspase-3 expressions (p < 0.05). Additionally, we observed basal membrane thickening in glomerules, intense electron deposition in the subendothelial region, and atypical folds in podocyte pedicels. Amifostine, curcumin, and melatonin reduced the increases in serum urea and serum creatinine levels following cisplatin administration and reduced the levels of TNS, HPS, NF-κB/p65, 8-OHdG, and caspase-3 expressions (p < 0.05). ROS-scavenging antioxidants may be a promising means of preventing acute kidney disease in patients using cisplatin in the treatment of malignant tumors.

Protective effects of amifostine, curcumin and caffeic acid phenethyl ester against cisplatin-induced testis tissue damage in rats.

Cisplatin is an effective antineoplastic drug that is usually used to treat a number of different types of cancer in the clinic. One of the most notable side effects of cisplatin use is infertility. The present study was designed to determine the non-oxidative testicular effects caused by the use of cisplatin in rats. The rats were randomly allocated to the experimental groups. The untreated rats represented the control group (group I) and the treatment groups were as follows: cisplatin alone (group II), cisplatin+amifostine (group III), cisplatin+curcumin (group IV), and cisplatin+caffeic acid phenethyl ester (CAPE; group V). The present study observed that following cisplatin administration, the expression of nuclear factor-κB (NF-κβ)/p65, caspase-3 and 8-deoxyguanosine (8-OHdG) increased in germinal epithelium and Leydig cells. However, the expression of these markers decreased in groups III–V, most notably in the group treated with amifostine. cisplatin induced-damage was countered by amifostine and curcumin. The results revealed that the activation of NF-κB, caspase-3 and 8-OHdG had a significant role in cisplatin-induced testicular toxicity. Thus, amifostine, curcumin and, to a lesser extent, CAPE have the potential for use as therapeutic adjuvants in cisplatin-induced testis injury.

Reducing Gastrointestinal Toxicity Associated with Autologous Transplantation for Multiple Myeloma without Compromising Its Anti-Myeloma Effect

Early autologous hematopoietic stem cell transplantation (auto-HCT) is recommended for transplant-eligible patients (pts) with newly diagnosed multiple myeloma (MM). However, gastrointestinal toxicities, i.e., oral mucositis (OM), nausea and diarrhea, are the major limitation to the use of auto-HCT especially in the elderly population which constitute a significant proportion of MM pts, where the median age at diagnosis is 68 years. There is an unmet need for measures to minimize non-hematological toxicities without compromising melphalan anti-myeloma efficacy; this could lead to expansion of transplant eligibility to older pts. Amifostine, a FDA-approved cytoprotective agent to prevent OM for Head and Neck cancer, may reduce HDM-associated GI toxicity. We conducted a case-control study comparing auto-HCT with or without amifostine for MM pts.Methodspre-transplant amifostine has been incorporated to standard protocol for all MM patients underwent auto-HCT at University Hospitals Cleveland Medical Center (UH) for the last decade. One hundred and seven pts treated at UH who received amifostine, from January 2007 to July 2014, were compared to 114 matched-control pts treated at MD Anderson Cancer Center (MDACC) without use of this agent. The institutional review boards at both institutions approved the study. Amifostine 740 mg/m2 was administered as a bolus infusion at 24 hours and 15 minutes before HDM. All pts received ice chips peri-melphalan infusion. Survival outcomes were measured from the date of auto-HCT to the date of disease relapse or progression, Survival distribution was estimated using Kaplan-Meier methods. The effect of treatment on OS and PFS was estimated using a Cox model after controlling for the effects of age, gender, and number of prior therapies, time from diagnosis to transplant, Eastern Cooperative Oncology Group (ECOG) performance status and number of infused CD34+ cells.ResultsPts' characteristics were similar in both groups.Median follow-up of surviving pts was 35 (range 2-100) months in both cohorts. Amifostine therapy was well tolerated without any serious adverse effects. There was no significant difference between all-grade OM, nausea or vomiting between the two cohorts. However, > grade II GI toxicities were significantly lower in the amifostine group as follows: OM: 27.1% vs 47.4% (P=0.002), diarrhea: 56.1% vs. 72.7% (P=0.006), nausea: 31.8% vs. 86.0% (P=0.0001) and vomiting: 18.7% vs. 52.6%, (P=0.0001) (Figure-1) (Table-1). Median time to platelet engraftment was similar between the two groups while neutrophil engraftment period was shorter with use of amifostine (10 vs. 11 days, P=0.011) (Table-2). Multivariable logistic regression showed that use of amifostine pre-transplant was associated with a significant decrease in OM, diarrhea, nausea and vomiting. Pts who received amifostine and melphalan developed grade ≥ II OM significantly less often than those given melphalan alone with odds ratio (OR) = 0.366 (95% CI: 0.196-0.685, P=0.001; Table 3). Female gender was associated with a significant increase in OM, nausea and vomiting. Female pts were more likely to develop grade ≥ II OM with OR of 1.967 (P=0.017). Similarly, an ECOG performance status (PS) of ≥ 2 was associated with a significant increase in OM and diarrhea. For every additional score of ECOG, the risk of having grade ≥ II OM increased 1.89 fold (p=0.015). Subgroup analysis of grade II and higher OM rates are shown in Table-4. Use of amifostine was associated with reduced grade II or higher GI toxicity after adjusting for the effects of age, gender, number of prior therapies, time from diagnosis to transplant, ECOG PS and infused CD34 cell dose. There was no detrimental effect of amifostine on progression-free or overall survival.ConclusionsOur analysis indicates that the use of two amifostine doses of 740 mg/m2 before auto-HCT is safe and associated with significant reduction in grade II and higher GI toxicities without any deleterious effect on engraftment or anti-myeloma efficacy. Amifostine use could conceivably allow further melphalan dose-intensification for pts with resistant or high-risk disease. Also, pre-treatment with amifostine potentially could expand the utilization of auto-HCT for modestly frail MM pts that might not be considered eligible for this treatment modality. The protective effect of amifostine should be confirmed in randomized trial. [Display omitted] DisclosuresMalek:Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. Cooper:Novartis: Research Funding. Caimi:Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau; Seattle Genetics: Equity Ownership. De Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding.

Protective effect of amifostine on busulfan induced DNA damage in human hepatoma cells

Busulfan is one of the most effective chemotherapeutic agents used for the treatment of chronic myeloid leukemia. However, as a bifunctional alkylating agent, during clinical use several side effects may occur. In addition, several in vivo and in vitro studies of busulfan have shown a range of genotoxic effects including DNA strand break and inhibition of DNA synthesis. Amifostine, an organic thiophosphate compound, has been shown to exert an important cyto-protective effect in many tissues. The aim of this study was to explore whether amifostine protects against busulfan-induced genotoxicity in HepG2 cell line. Our results showed that amifostine reduced the genotoxic effects of busulfan significantly in both type of experiment conditions, as measured via comet assay. Furthermore, amifostine decreased the intracellular ROS generation induced by busulfan and also increased the intracellular GSH levels in HepG2 cells. Altogether, our results suggest a protective action of amifostine against busulfan cytotoxicity and genotoxicity via various pathways. The most protective effect was observed with amifostine when it was administrated 24 h before busulfan treatment.

Structural and functional damages of whole body ionizing radiation on rat brain homogenate membranes and protective effect of amifostine

Purpose: To investigate the effects of whole body ionizing radiation at a sublethal dose on rat brain homogenate membranes and the protective effects of amifostine on these systems at molecular level.Materials and methods: Sprague-Dawley rats, in the absence and presence of amifostine, were whole-body irradiated at a single dose of 8 Gy and decapitated after 24 h. The brain homogenate membranes of these rats were analyzed using Fourier Transform Infrared (FTIR) spectroscopy.Results: Ionizing radiation caused a significant increase in the lipid to protein ratio and significant decreases in the ratios of olefinic = CH/lipid, CH2/lipid, carbonyl ester/lipid and CH3/lipid suggesting, respectively, a more excessive decrease in the protein content and the degradation of lipids as a result of lipid peroxidation. In addition, radiation changed the secondary structure of proteins and the status of packing of membrane lipid head groups. Furthermore, it caused a decrease in lipid order and an increase in membrane fluidity. The administration of amifostine before ionizing radiation inhibited all the radiation-induced alterations in brain homogenate membranes.Conclusions: The results revealed that whole body ionizing radiation at a sublethal dose causes significant alterations in the structure, composition and dynamics of brain homogenate membranes and amifostine has a protective effect on these membranes.

Does amifostine reduce metabolic rate? Effect of the drug on gas exchange and acute ventilatory hypoxic response in humans.

Amifostine is added to chemoradiation regimens in the treatment of many cancers on the basis that, by reducing the metabolic rate, it protects normal cells from toxic effects of therapy. We tested this hypothesis by measuring the metabolic rate (by gas exchange) over 255 min in 6 healthy subjects, at two doses (500 mg and 1000 mg) of amifostine infused over 15 min at the start of the protocol. We also assessed the ventilatory response to six 1 min exposures to isocapnic hypoxia mid-protocol. There was no change in metabolic rate with amifostine as measured by oxygen uptake (p = 0.113). However in carbon dioxide output and respiratory quotient, we detected a small decline over time in control and drug protocols, consistent with a gradual change from carbohydrate to fat metabolism over the course of the relatively long study protocol. A novel result was that amifostine (1000 mg) increased the mean ± SD acute hypoxic ventilatory response from 12.4 ± 5.1 L/min to 20.3 ± 11.9 L/min (p = 0.045). In conclusion, any cellular protective effects of amifostine are unlikely due to metabolic effects. The stimulatory effect on hypoxic ventilatory responses may be due to increased levels of hypoxia inducible factor, either peripherally in the carotid body, or centrally in the brain.

Protective effects of amifostine on ischemia-reperfusion injury of rat kidneys

Objectives:Amifostine is a drug which can eliminate free oxygen radicals that appear in the body after radiation or chemotherapeutic agent exposure. It is used to decrease the renal toxicity of cisplatin. The aim of this study was to determine the role of amifostine in warm ischemia kidney model for prevention of ischemia/reperfusion injury and also to find out the mechanism for prevention from ischemia/reperfusion injury if such an effect does exist.Materials and Methods:Adult female rats (n = 40) that used in our study were divided into three groups. Group 1: Control (n = 8), group 2: Ischemia-control (n = 16), group 3: Amifostine treated (n = 16). The effect of amifostine on ischemia/reperfusion injury investigated in rat kidneys.Results:At the 7th day, blood urea nitrogen level was statistically significantly higher in ischemia-control group than all groups (P = 0.001) and mean serum creatinine levels were found to be the highest in ischemia-control group (P = 0.091). Mean malondialdehyde levels in left kidneys removed on the 7th day were not significantly different (P = 0.105) at all three groups. Between ischemia-control group and amifostine group, there was a significant difference in reduced glutathione (GSH) levels (P = 0.001). In amifostine group, grade 4 necrosis was not detected neither on 7th day nor day 0.Conclusion:Amifostine could decrease the degree and severity of necrosis after reperfusion. Amifostine could not prevent membrane lipid peroxidation caused by superoxide anion radicals in kidney but they could protect tissues from the harmful effects of ischemia/reperfusion injury by increasing the level of reduced GSH which is a well-known oxygen radical eliminator.

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

The protective effect of amifostine against cyclophosphamide (CP) was evaluated on mouse oocytes. Female mice were divided into four groups as follows: group1: cyclophosphamide (CP) (75mg/kg, i.p) injection, group2: amifostine (250mg/kg, i.p) injection, group3: amifostine (250mg/kg, i.p) administered prior to CP (75mg/kg, i.p) injection, Control group with injection of saline. About 21days after injection, in vitro maturation (IVM) of oocytes was recorded. Furthermore the percentage of aneuploid oocytes was determined. 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. 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.

PO-49: Protective Effects of Amifostine and L-Carnitine Against Radiation induced Acute Testicular toxicity

PO-49: Protective Effects of Amifostine and L-Carnitine Against Radiation induced Acute Testicular toxicity

Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: An FTIR microspectroscopic imaging study

Amifostine is the only approved radioprotective agent by FDA for reducing the damaging effects of radiation on healthy tissues. In this study, the protective effect of amifostine against the damaging effects of ionizing radiation on the white matter (WM) and grey matter (GM) regions of the rat brain were investigated at molecular level. Sprague–Dawley rats, which were administered amifostine or not, were whole-body irradiated at a single dose of 800cGy, decapitated after 24h and the brain tissues of these rats were analyzed using Fourier transform infrared microspectroscopy (FTIRM). The results revealed that the total lipid content and CH2 groups of lipids decreased significantly and the carbonyl esters, olefinicCH and CH3 groups of lipids increased significantly in the WM and GM after exposure to ionizing radiation, which could be interpreted as a result of lipid peroxidation. These changes were more prominent in the WM of the brain. The administration of amifostine before ionizing radiation inhibited the radiation-induced lipid peroxidation in the brain. In addition, this study indicated that FTIRM provides a novel approach for monitoring ionizing radiation induced-lipid peroxidation and obtaining different molecular ratio images can be used as biomarkers to detect lipid peroxidation in biological systems.

Baş ve Boyun Kanseri Hastalarında Radyasyonun Akut ve Geç Yan Etkileri Üzerine Amifostinin Etkisi

Objective: We aimed to investigate the effect of amifostine on acute and late side effects, and its tolerability in head and neck cancer patients treated with radiotherapy (RT). Material and Methods: The study included 87 patients with primary head and neck cancers and cervical lymph node metastases from unknown primary cancers treated with RT alone or combined with chemotherapy (CT). Forty-one patients (47%) received amifostine combined with RT (ART group) and 46 patients (52%) received RT without amifostine (RT group). The patients were evaluated every week during the treatment and at month 1 and 2 after the completion of RT for acute side effects and month 3, 6, 9, 12, and 24 after the treatment for late side effects according to SOMA/LENT scale. Amifostine was administered prior to RT, along with anti-emetic prophylaxis. The two groups were compared with the Student\\s t and Mann-Whitney U and Chi-square tests. Results: The ART group had significantly less toxicity (grade 1 mucositis, grade 2 fibrosis) than patients in the RT group (p=0.001, p=0.03, respectively). At week 3 of RT grade 2 mucositis developed in two patients (5%) in the ART group and 10 patients (22%) in the RT group (p=0.02). The protective effect of amifostine on skin reactions developed at week 4 of RT (p=0.05). Grade 3 xerostomia at 9, 12, and 15 months of follow-up (p=0.02, p=0.02, and p=0.02, respectively), grade 2 xerostomia at 18 and 24 months (p=0.02 and p=0.01, respectively) and fibrosis at 15, 18 and 24 months (p=0.05, p=0.02 and p=0.02, respectively) decreased markedly in the ART group compared with the RT group. Emesis was the most common adverse effect of amifostine. Conclusion: Daily administration of amifostine during RT was effective in avoiding late grade 2-3 xerostomia, as well as grade 2 fibrosis.

Induction of cellular antioxidant defense by amifostine improves ventilator-induced lung injury*

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 induces reactive oxygen species production and oxidative stress in the lung, which plays a major role in the pathogenesis of ventilator-induced lung injury. Amifostine attenuates oxidative stress and improves lipopolysaccharide-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 before high tidal volume ventilation (30 mL/kg, 4 hrs) at day 4. Pulmonary endothelial cell cultures were exposed to pathologic cyclic stretching (18% equibiaxial stretch) and thrombin in a previously verified two-hit model of in vitro ventilator-induced lung injury. Three-day amifostine preconditioning before high tidal volume attenuated high tidal volume-induced protein and cell accumulation in the alveolar space judged by bronchoalveolar lavage fluid analysis, decreased Evans Blue dye extravasation into the lung parenchyma, decreased biochemical parameters of high tidal volume-induced tissue oxidative stress, and inhibited high tidal volume-induced activation of redox-sensitive stress kinases and nuclear factor-kappa B inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 expression and increased superoxide dismutase and catalase enzymatic activities in the animal and endothelial cell culture models of ventilator-induced lung injury. Amifostine preconditioning activates lung tissue antioxidant cell defense mechanisms and may be a promising strategy for alleviation of ventilator-induced lung injury in critically ill patients subjected to extended mechanical ventilation.

Protective Effects of Amifostine and Cyclooxygenase-1 Inhibitor against Normal Human Epidermal Keratinocyte Toxicity Induced by Methotrexate and 5-Fluorouracil

Our study aimed to find more effective protective agents against mucosa toxicity induced by methotrexate and 5-fluorouracil. We focused on the relationship between oral mucositis and keratinocyte injury and examined methotrexate and 5-fluorouracil-induced cytotoxicity in normal human epidermal keratinocyte cell lines. Cell viability and superoxide radical activity were measured based on converting WST-1 (4-[3-(4-indophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzen disulfonate) to a water-soluble formazan dye. DNA synthesis by 5-bromo-2'-deoxyuridine incorporation was measured as an indirect parameter of cell proliferation. Allopurinol and amifostine were used as the radical scavengers. l-glutamine was used as a mucosa-protective agent. A cyclooxygenase inhibitor interrupting the production of hydroxyl radicals in the arachidonic acid cascade was also examined. 5-fluorouracil and methotrexate caused cytotoxicity due to the activation of intracellular superoxide radicals specifically on normal human epidermal keratinocytes. From the electron spin resonance study, it was found that allopurinol was a superoxide radical scavenger, while amifostine was hydroxyl radical scavenger. Allopurinol showed no effect on the cytotoxicity due to 5-fluorouracil and methotrexate. The cell injury induced by methotrexate was restored by amifostine. However, the cell injury induced by 5-fluorouracil was markedly recovered by a selective cyclooxygenase-1 inhibitor compared to amifostine. It was suggested that amifostine and cyclooxygenase-1 inhibitor could be useful protective agents against methotrexate and 5-fluorouracil chemotherapeutic toxicity. Additionally, this in vitro cell injury model using normal human epidermal keratinocytes may be useful for understanding the pathophysiology of oral mucositis induced by chemotherapeutic agents.

Amifostine, a Radioprotectant Agent, Protects Rat Hepatic Microsomal Membranes Against Ionizing Radiation Induced Damage

In the present study, the protective effect of amifostine (WR-2721), which is the only approved radioprotective agent by the Food and Drug Administration (FDA), was investigated against the deleterious effects of ionizing radiation on rat liver microsomal membranes at molecular level. To achieve this, Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated using Cobalt-60 irradiator at a single dose of 800 cGy, decapitated after 24 h and the microsomal membranes isolated from the livers of these rats were analyzed using FTIR spectroscopy. The results revealed that ionizing radiation caused a significant increase in the concentration of lipids whereas amifostine treatment restored the lipid content of microsomal membranes to control values. In addition, the significant increase in lipid order and a significant decrease in membrane dynamics resulting from ionizing radiation were prevented by amifostine. While ionizing radiation caused a significant decrease in the lipid to protein ratio, amifostine injection before radiation, maintained this ratio as in the control group. Furthermore, ionizing radiation-induced variations in protein secondary structure were restored by amifostine. In conclusion, the data obtained in this study indicate that amifostine administration to the rats prior to whole body irradiation protects liver microsomal membranes against the radiation induced damages. Supported by TUBITAK, (SBAG-2939) and by the METU (BAP-2006-07-02-0001).

Amifostine reduces lung vascular permeability via suppression of inflammatory signalling

Despite an encouraging outcome of antioxidant therapy in animal models of acute lung injury, effective antioxidant agents for clinical application remain to be developed. The present study investigated the effect of pre-treatment with amifostine, a thiol antioxidant compound, on lung endothelial barrier dysfunction induced by Gram-negative bacteria wall-lipopolysaccharide (LPS). Endothelial permeability was monitored by changes in transendothelial electrical resistance. Cytoskeletal remodelling and reactive oxygen species (ROS) production was examined by immunofluorescence. Cell signalling was assessed by Western blot. Measurements of Evans blue extravasation, cell count and protein content in bronchoalveolar lavage fluid were used as in vivo parameters of lung vascular permeability. Hydrogen peroxide, LPS and interleukin-6 caused cytoskeletal reorganisation and increased permeability in the pulmonary endothelial cells, reflecting endothelial barrier dysfunction. These disruptive effects were inhibited by pre-treatment with amifostine and linked to the amifostine-mediated abrogation of ROS production and redox-sensitive signalling cascades, including p38, extracellular signal regulated kinase 1/2, mitogen-activated protein kinases and the nuclear factor-kappaB pathway. In vivo, concurrent amifostine administration inhibited LPS-induced oxidative stress and p38 mitogen-activated protein kinase activation, which was associated with reduced vascular leak and neutrophil recruitment to the lungs. The present study demonstrates, for the first time, protective effects of amifostine against lipopolysaccharide-induced lung vascular leak in vitro and in animal models of lipopolysaccharide-induced acute lung injury.

Amifostine (Wr-2721) Prevents Indomethacin-Induced Gastric Damage in Rats: Role of Non-Protein Sulfhydryl Groups and Leukocyte Adherence

This study was designed to evaluate the protective effect of amifostine on indomethacin-induced gastric damage, and the role of increased gastric non-protein sulfhydryl groups (NP-SH) and decreased leukocyte adherence in this event. Wistar rats were pretreated with amifostine (10, 30, or 90 mg/kg intraperitoneal (i.p.) or subcutaneous (s.c.)) or saline. After 30 min, the rats received indomethacin (20 mg/kg, by gavage) and were then killed 3 hr later. Macroscopic and microscopic gastric damage, concentration of gastric NP-SH, prostaglandin E2 (PGE2), and mesenteric leukocyte adherence (intravital microscopy) were assessed. Amifostine prevented significantly (P < 0.05), macroscopic or microscopic, indomethacin-induced gastric damage, and increased gastric NP-SH, in a dose-dependent manner, with a maximal effect at a dose of 90 mg/kg. Subcutaneous, but not i.p., amifostine administration decreased (P < 0.05) the indomethacin-induced increase in leukocyte adherence. Indomethacin-induced PGE2 depletion was not reversed by amifostine. Amifostine has a protective effect against indomethacin-induced gastropathy by increasing gastric NP-SH and decreasing leukocyte adherence.

Is Amifostine Effective on the Protection of Mitoxantrone-Induced Acute Cardiotoxicity? A Biochemical and Histopathological Experimental Study.

Background: Mitoxantrone (MTX), an anthracenedione derivate, is used in the treatment of several malignancies. One of the most important adverse effects is dose-dependent cardiotoxicty. Myocardial adrenergic imbalance, oxygen free radicals, tumor necrosis factor-alpha, interleukin-2, and increased intracellular calcium may play role in the development of anthracycline-induced cardiotoxicity.Aim: In this study, the roles of lipid peroxidation, oxygen free radicals and protective enzymes, and the protective effect of amifostine (AMI) were evaluated using biochemical and histopathological methods on mitoxantrone-induced acute cardiotoxicity in rat heart.Materials and method: This study was performed on 36 male Wistar rats. Rats were divided to equal 6 groups:Control group was received as serum saline 10 ml/kg, intraperitoneally (IP),AMI group 200 mg/kg IP,MTX 2.5 mg/kg group IP,MTX 5 mg/kg group IP,MTX 2.5 mg/kg+AMI 200 mg/kg group IP, andMTX 5 mg/kg+AMI 200 mg/kg IP.AMI was performed before 30 min. MTX in last two groups. Creatine kinase-myocardial band (CK-MB) and troponin-T were analyzed at pre-study, 1st, and 7th days. Rats were killed after 7 days. Malondialdehyde (MDA), catalase, superoxide dismutase (SOD), total glutathione (GSH), and glutathione peroxidase (Gpx) were analyzed with spectrophotometric method in rat heart. Fibrosis, inflammation, degeneration, apoptosis, and calcium deposits in myocardium were evaluated with pathological examination and scoring system. This study was approved by university animal ethic committee and supported by University.Results: CK-MB and troponin-T levels were not different between six groups and three assays (p>0.05). MDA levels in MTX were higher than those of control and AMI goups (p<0.05, p<0.001, respectively). Moreover MDA levels in AMI+MTX groups were not different compared to control and AMI groups (p>0.05). SOD levels in MTX 5+AMI group was higher than controls (p<0.005). Catalase levels in both MTX and MTX+AMI groups significantly increased than those of control and AMI goups (p<0.001, p<0.05, respectively). Total GSH levels in MTX and MTX+ AMI groups higher than those of control and AMI groups (p<0.001, p<0.005, respectively). Gpx levels in MTX 5+AMI were lower compared to MTX 2.5 group (p<0.05). Calcium deposits were not detected in any rat. Myocardial fibrosis score in MTX 2.5 groups was higher than those of control (p<0.001), AMI (p<0.05), MTX 5 (p<0.005), and MTX 5+AMI (p<0.005) groups. Billingham score for myocardial degeneration in all groups was higher than controls (p<0.001). Apopitosis score in MTX 2.5 group increased compared to control, AMI (p<0.001) and MTX 5 (p<0.05) groups. Inflammation score in AMI, MTX 2.5 and 5 groups was higher than controls (p<0.001). Whereas inflammation in MTX+AMI groups decreased than those of MTX 2.5 group (p<0.05,p<0.001, respectively).Conclusion: While MTX causes inflammation, fibrosis, degeneration, and apopitosis in rat heart, it induces lipid peroxidation. Moreover AMI may protect myocardium from MTX-induced lipid peroxidation and histopathological damage.

The relationship between the protective effect of amifostine and decreased intercellular adhesion molecule 1 expression

Purpose The objective of our study was to characterize the relationship between the protective effect of amifostine and decreased intercellular adhesion molecule 1 (ICAM-1) expression in early-phase, radiation-induced otitis media and to illustrate the possible mechanism of early-phase radiation-induced otitis media. Materials and methods A comparison study of middle ear tissue was performed by the expression of ICAM-1 and the electron microscope from total 38 guinea pigs. Group A, consisting of 2 pigs, was used as control, and these pigs were not irradiated. Groups B, C, D, and E, consisting of 9 pigs each, were irradiated. Sterile saline was administered intraperitoneally to the pigs in groups B and D before irradiation, and amifostine was administered intraperitoneally as an aqueous solution 30 minutes before irradiation to the pigs in groups C and E. The pigs in groups B and C were killed on the second day after irradiation, and the pigs in groups D and E were killed 30 days after irradiation. Results Intercellular adhesion molecule 1 was strongly expressed in the middle ear mucosa of the irradiated pigs after a 45-Gy dose of radiation was administered. Enhanced ICAM-1 expression was accompanied by pathomorphologic changes in the middle ear tissue. Scanning electron microscopy demonstrated the changes. Intercellular adhesion molecule 1 expression in the mucosa of the groups killed on the second day was stronger than that in the mucosa of the groups killed 30 days after irradiation. Amifostine protected the middle ear from radiation injury, and we found that the expression of ICAM-1 in the middle ear mucosa was down-regulated. However, slight expression of ICAM-1 remained 30 days after irradiation. Conclusions Irradiation increased the expression of ICAM-1 in the middle ear mucosa. Amifostine protected the middle ear from early irradiation injury. There was a relationship between oxygen free radicals derived from irradiation and up-regulation of ICAM-1 expression. Continuous ICAM-1 expression might be related to stenosis of the eustachian tube.

The Protective Effects of Amifostine on Adriamycin-Induced Acute Cardiotoxicity in Rats

Free oxygen radicals and lipid peroxidation are responsible for adriamycin-induced cardiotoxicity. Amifostine is a scavenger of free radicals and may function as a selective cytoprotective agent. The aim of this study was to investigate the effects of amifostine on adriamycin-induced lipid peroxidation and the levels of protective enzymes in the heart. Male Wistar rats were randomly allocated to three groups: pretreated, untreated, and control (n=10 in each group). Rats were pretreated with an intraperitoneal injection of amifostine (200 mg/kg) 30 min before the injection of adriamycin. The pretreated rats were given an intraperitoneal injection of adriamycin (10 mg/kg) and were sacrificed after 72 h. Likewise, rats received intraperitoneal injection of adriamycin (untreated) or saline (control). The hearts were removed for the analyses of malondialdehyde (MDA), reduced glutathione (GSH) and catalase. MDA levels were increased (p<0.005) in the heart tissues of untreated rats compared to control, while GSH and catalase levels were decreased (p<0.05 and p<0.001, respectively) in untreated animals. In amifostine-preatreated group, MDA levels were lower (p<0.01), and GSH and catalase levels were higher (p<0.05 for both) than the untreated group. GSH levels were even higher in the amifostine-pretreated group compared to control (p<0.01), although catalase levels were significantly lower in the pretreated group (p<0.05). These results indicate that amifostine decreases adriamycin-induced lipid peroxidation and increases the levels of the protective enzymes in the heart tissue. Therefore, amifostine may ameliorate the adriamycin-induced acute cardiotoxicity.