Amifostine Group Research Articles

VALD-2 mitigates cisplatin-induced acute kidney injury: Mechanistic insights into oxidative stress modulation and inflammation suppression.

This study explores the compelling antitumor properties of VALD-2, a synthetic Schiff base ligand known for its low toxicity. The focus is on investigating VALD-2's protective role against cisplatin-induced acute kidney injury (AKI) in mice, with a specific emphasis on mitigating oxidative stress and inflammation. The study involves daily intraperitoneal injections of amifostine or VALD-2 over 7 days to establish an AKI model. Subsequently, mice were assigned to normal control, cisplatin group, cisplatin + amifostine group, and cisplatin + VALD-2 10 mg/kg group, cisplatin + VALD-2 20 mg/kg, and cisplatin + VALD-2 40 mg/kg. Kidney injury is assessed through serum blood urea nitrogen (BUN) and creatinine (Cr) activity assays. Levels of inflammatory factors,tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in kidney tissue of mice were assessed through enzyme-linked immunosorbent assay (ELISA). The protective effect of VALD-2 is further examined through HE staining to observe pathological changes in kidney injury. The ultrastructural changes of renal cells and tubular epithelial cells were observed by electron microscopy under experimental conditions, indicating the effect of VALD-2 on reversing cisplatin-induced renal injury. The study delves into VALD-2's protective mechanisms against cisplatin-induced kidney injury by using western blot analysis to assess the expression levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) in kidney tissues. VALD-2 demonstrates significant improvement in cisplatin-induced AKI, as evidenced by increased BUN and Cr levels. It effectively protects kidney tissue from oxidative damage, enhancing SOD and GSH-Px activities while reducing MDA levels. The study also reveals a decrease in TNF-α and IL-6 levels, supported by ELISA results, and histological findings confirm anti-nephrotoxic effects. Western blot analysis shows an upregulation of antioxidant enzymes (SOD, GSH-Px) and a reduction in MDA production. VALD-2 emerges as a promising mitigator of cisplatin-induced AKI, showcasing its ability to enhance oxidative stress-related protein expression. The findings suggest VALD-2 as a potential therapeutic agent for protecting against cisplatin-induced kidney injury.

The nephroprotective effect of amifostine in a cecal ligation-induced sepsis model in terms of oxidative stress and inflammation.

Sepsis is responsible for more than 5 million deaths worldwide every year. The purpose of this study was to use amifostine to reduce acute kidney injury developing as a result of sepsis. Thirty Sprague Dawley rats were divided into three equal groups - a healthy control group (Group 1), cecal ligation and puncture group (CLP, Group 2), and a CLP + amifostine (AMF) group receiving a total of 200 mg/kg AMF intraperitoneally (i.p.) 15 min before sepsis induction (Group 3). Total thiol levels decreased while malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB/p65), and interleukin (IL)-1β, and IL-6 levels increased in the CLP group. We also observed degeneration in renal corpuscles, necrotic tubules, polymorphonuclear leukocyte inflammation, and vascular congestion. In the amifostine group, total thiol levels in tissue increased, while MDA, TNF-α, NF-кB/p65, IL-1β, and IL-6 levels, necrotic renal tubules, and inflammation decreased. Amifostine prevented sepsis-related acute kidney injury by reducing inflammation and oxidative stress.

Could Amifostine Prevent Experimental Radiotherapy-Induced Acute Pericarditis?

Amifostine is a powerful antioxidant that is one of the documented three chemo-radio prototectants recommended for clinical use. There is no data exploring amifostine in prevention of acute pericardial damage. We aimed to investigate whether amifostine has protective effect against acute pericardial injury due to radiotherapy in an experimental rat model. Twenty-four rats were divided into four groups: control group, radiotherapy-only group, amifostine-only group, radiotherapy+amifostine group. In groups receiving radiotherapy, hearts were irradiated with a Co 60 teletherapy device at a distance of 80 cm and 20 Gy at a depth of 2 cm. Thirty minutes before interventions, 200 mg/kg amifostine or same volume 0.9% NaCl were administered intraperitoneally. Subjects were sacrificed 24 hours after the procedure. Pericardial histopathological changes were investigated by light microscopy. There was focal inflammation of >= 50% in all rats exposed-to-radiotherapy. All groups receiving radiotherapy revealed a significant increase in pericardial inflammation compared to the groups that did not receive irradiation (p<0.05). There was no difference between the radiotherapy-only group and amifostine+radiotherapy group for pericardial inflammatory response (p>0.05). Acute pericarditis was detected in all rats receiving radiotherapy. There was no positive effect of amifostine administration before radiotherapy on acute pericardial inflammation.

The role of amifostine in preventing radiotherapy induced testicular tissue damage in rats

ABSTRACT The germinal epithelium of the adult testis is susceptible to radiation induced damage. Amifostine is a drug used to prevent the side effects of radiotherapy (RT) and chemotherapy. We investigated the protective role of amifostine against RT induced damage to rat testis using the TUNEL assay. We used adult male rats divided equally into four groups: untreated control group; amifostine group, 200 mg/kg amifostine/day for 3 days; RT-saline group, 2 Gy/day local irradiation of testes for 3 days; RT-amifostine group, 2 Gy/day local irradiation of testes for 3 days plus 200 mg/kg amifostine 30 min before each irradiation. Four weeks after treatment, rats were sacrificed for histological examination and apoptosis was assessed using the TUNEL method. The TUNEL staining density was obtained by evaluating separate seminiferous tubules selected randomly from each section using the stereological fractionator method. Apoptosis in the seminiferous tubules in the control group and amifostine groups were evaluated as spontaneous. Frequent apoptosis was observed in the RT-saline group; a statistically significant difference was observed between the RT treated and untreated groups. Administration of amifostine 30 min before RT protected the testicular germ cells against apoptosis.

Therapeutic Interventions to Reduce Radiation Induced Dermal Injury in a Murine Model of Tissue Expander Based Breast Reconstruction.

Radiation therapy (XRT) induced dermal injury disrupts type I collagen architecture. This impairs cutaneous viscoelasticity, which may contribute to the high rate of complications in expander-based breast reconstruction with adjuvant XRT. The objective of this study was to further elucidate the mechanism of radiation-induced dermal injury and to determine if amifostine (AMF) or deferoxamine (DFO) mitigates type I collagen injury in an irradiated murine model of expander-based breast reconstruction. Female Lewis rats (n = 20) were grouped: expander (control), expander-XRT (XRT), expander-XRT-AMF (AMF), and expander-XRT-DFO (DFO). Expanders were surgically placed. All XRT groups received 28 Gy of XRT. The AMF group received AMF 30 minutes before XRT, and the DFO group used a patch for delivery 5 days post-XRT. After a 20-day recovery period, skin was harvested. Atomic force microscopy and Raman spectroscopy were performed to evaluate type I collagen sheet organization and tissue compositional properties, respectively. Type I collagen fibril disorganization was significantly increased in the XRT group compared with the control (83.8% vs 22.4%; P = 0.001). Collagen/matrix ratios were greatly reduced in the XRT group compared with the control group (0.49 ± 0.09 vs 0.66 ± 0.09; P = 0.017). Prophylactic AMF demonstrated a marked reduction in type I collagen fibril disorganization on atomic force microscopy (15.9% vs 83.8%; P = 0.001). In fact, AMF normalized type I collagen organization in irradiated tissues to the level of the nonirradiated control (P = 0.122). Based on Raman spectroscopy, both AMF and DFO demonstrated significant differential protective effects on expanded-irradiated tissues. Collagen/matrix ratios were significantly preserved in the AMF group compared with the XRT group (0.49 ± 0.09 vs 0.69 ± 0.10; P = 0.010). β-Sheet/α-helix ratios were significantly increased in the DFO group compared with the XRT group (1.76 ± 0.03 vs 1.86 ± 0.06; P = 0.038). Amifostine resulted in a significant improvement in type I collagen fibril organization and collagen synthesis, whereas DFO mitigated abnormal changes in collagen secondary structure in an irradiated murine model of expander-based breast reconstruction. These therapeutics offer the ability to retain the native microarchitecture of type I collagen after radiation. Amifostine and DFO may offer clinical utility to reduce radiation induced dermal injury, potentially decreasing the high complication rate of expander-based breast reconstruction with adjuvant XRT and improving surgical outcomes.

Protective effects of curcumin on radioiodine-induced salivary gland dysfunction in mice.

Radioiodine (RI) treatment is widely used in patients with differentiated thyroid cancer. However, RI exposure often induces salivary gland (SG) dysfunction. In this study, we investigated the effect of curcumin on RI-induced SG dysfunction in mice. Mice were assigned to one of four groups (n=6 per group) as follows: normal control, RI only, RI+curcumin, and RI+amifostine group. Salivary flow rate, lag time, and changes in 99m Tc (technetium)-pertechnetate uptake and excretion were measured, and changes in SG morphology and histology were analysed. Salivary epidermal growth factor content, amylase, and superoxide dismutase (SOD) activities were also measured. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to assess SG apoptosis, and the expression of apoptosis-related protein was determined by western blotting. The reduced salivary flow rate and prolonged lag time in the RI group was restored by treatment with curcumin or amifostine. In the histological analysis, compared with the RI group, RI+curcumin and RI+amifostine groups had more mucin-rich acini and less periductal fibrosis. Compared with the RI group, RI+curcumin and RI+amifostine groups showed evidence of tissue remodelling, with a greater number of salivary epithelial cells (AQP-5-positive), SG ductal cells (CK18-positive), endothelial cells (CD31-positive), and myoepithelial cells (α-SMA-positive). RI+curcumin and RI+amifostine groups alleviated RI-induced cell death, demonstrating antiapoptotic effect, compared with the RI group. Both SOD activity and the protein expression levels of SOD2 were higher in the RI+curcumin and RI+amifostine groups than in the RI group. Our results demonstrate that curcumin ameliorates RI-induced SG dysfunction in mice.

Protective Effect of Ginseng on Salivary Dysfunction Following Radioiodine Therapy in a Mouse Model.

Following radioiodine (RI) therapy, oxidative stress is a putative damage mechanism resulting in salivary gland (SG) dysfunction. Since ginseng is a known anti-oxidative herb, we examined the SG radioprotective effects of Korea red ginseng (KRG) in a mouse model, when administered prior to RI. Four-week-old mice (n = 60) were divided into four groups: (1) normal control, (2) RI only treated (0.01 mCi/g, orally), (3) KRG administered (0.2 mg/g, intraperitoneal injection) 0.5 and 24 hours before RI, and (4) amifostine-treated group (0.2 mg/g, intraperitoneally) 0.5 hour before RI. The salivary lag times and flow rates were assessed, and sampled tissues were subjected to histologic examinations including hematoxylin and eosin and immunohistochemical staining. Apoptosis was examined by the terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling (TUNEL) assay, and excretion changes in salivary 99mTc pertechnetate were evaluated by single-photon emission computed tomography. The body weight of the KRG group was similar to the control group. Salivary lag times and flow rates in the RI + KRG group were faster than in the RI only group. There was no significant intergroup difference in the SG weight. The RI + KRG group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Salivary epithelial (aquaporin 5) and myoepithelial (smooth muscle actin) cells of the RI + KRG group were protected from radiation damage. Low 8-OhdG (oxidative stress biomarker) and high superoxide dismutase 2 (reactive oxygen species scavenger) immunostaining reactivity was detected in the RI + KRG group when compared with the RI only group. Fewer apoptotic cells were observed in the RI + KRG or amifostine group compared to the RI only group in the TUNEL assay. The 99mTc pertechnetate excretion level recovered in the KRG group. Pretreatment with KRG before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.

Histologic Improvements in Irradiated Bone Through Pharmaceutical Intervention in Mandibular Distraction Osteogenesis

Despite the relative surgical ease and reduced donor-site morbidity of distraction osteogenesis (DO) in comparison with free tissue transfer, DO is currently precluded as a reconstructive option for head and neck cancer (HNC) patients because of the destructive effects of radiotherapy (XRT). This study investigates the ability of a novel combined therapy (CT) of radioprotective amifostine (AMF) and angiogenic deferoxamine (DFO) to mitigate XRT-induced bone injury in a murine model of DO. Thirty male Sprague-Dawley rats were divided into 5 groups: DO (primary control), XRT (secondary control), AMF, DFO, and CT. With the exclusion of the DO group, all rats were administered a fractionated, human-equivalent XRT dose of 35Gy, comparable with 70Gy administered to HNC patients clinically. All groups underwent mandibular osteotomy and distraction to 5.1mm. After euthanasia administration on postoperative day 40, the mandibles were sectioned and stained with Gomori trichrome.Osteocyte number, bone volume, and osteoid volume were compared between all groups by analysis of variance (P<.05). All rats survived and were included in the final analysis. The XRT group exhibited substantial bone injury, evidenced by a decreased osteocyte number and bone volume, as well as an increase in immature osteoid volume, compared with DO controls.The AMF, DFO, and CT groups showed significant increases in osteocyte proliferation compared with the XRT group and were not statistically different from the DO group. Notably, the CT group showed remediation of XRT-induced impairment of bone maturation and exhibited significantly greater bone volume and reduced osteoid volume in comparison with all groups. Combined AMF and DFO treatment showed the capacity to remediate the deleterious effects of XRT, restore cellularity to nonirradiated levels, and surpass all groups in mature bone formation. Although further investigations of AMF and DFO are warranted, this study provides preliminary support for the potential use of DO in HNC patients through pharmaceutical facilitation of irradiated bone healing.

The radiation protection role of heparin-SOD conjugate in irradiated mice

Heparin-SOD conjugate (Hep-SOD) was prepared by modifying Cu,Zn-SOD with heparin. An acute radiation-induced mouse injury model was constructed to study the radiation protection effects of Hep-SOD conjugate. Fifty-six mice were randomly divided into seven groups: (I) normal control group; (II) irradiated control group; (III) positive control group (amifostine group, 300 mg/kg); (IV) SOD group (35000 U/kg); (V) high dosage of Hep-SOD group (70000 U/kg); (VI) medium dosage of Hep-SOD group (35000 U/kg); (VII) low dosage of Hep-SOD group (17500 U/kg). Drugs were intraperitoneally injected into each mouse 1 h before radiation except for the normal control group. All the irradiated groups were irradiated with 6 Gy. Organ indices, haematopoietic function indices, peripheral blood cells, liver function test, oxidative stress state and pathological observation were detected to study the effects of Hep-SOD on irradiated mice. Results showed that bone marrow suppression of irradiated mice could be reduced when treated by Hep-SOD before radiation. Oxidative stress detection and pathological observation of the liver and intestine showed that the damage caused by radiation was relieved when mice were treated with Hep-SOD before radiation. This study shows a new direction to prevent organisms from the damage caused by radiation.

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.

Effect of Amifostine on Sperm DNA Fragmentation and Testes after Radioiodine Treatment.

IntroductionRadioactive iodine (RAI) is commonly used for the treatment of hyperthyroidism caused by Graves’ disease or thyroid nodules. However, information available on the impact of RAI therapy on male gonadal function is scarce. This study aimed to determine any possible damage to testicular tissue and sperm quality caused by RAI therapy, and the radioprotective effect of amifostine against such damage.Material and MethodsIn total, 36 rats were randomly allocated to three groups, including a control group, RAI group (111 MBq Iodine-131), and RAI + amifostine group (111 MBq Iodine-131 and a single dose of 200 mg/kg amifostine). Blood and epididymal sperm samples were taken for hormone analyses and the evaluation of spermatological parameters. The TUNEL assay and haematoxylin-eosin were used to stain testicular tissue samples to detect histological changes and apoptosis.ResultsThe groups differed insignificantly for the testicular mass index and spermatozoa concentration. However, spermatozoa motility and percentage of viable spermatozoa were higher in the RAI + amifostine group, compared to the RAI group. Sperm DNA fragmentation and the index of apoptotic germ cells significantly decreased in the amifostine group, in comparison to the radioiodine group. While the testosterone levels showed no significant change, the follicle stimulating hormone (FSH) levels significantly decreased in the RAI + amifostine group.ConclusionAll histopathological parameters and some spermatological parameters showed that RAI therapy caused statistically significant damage of testicular tissue and this damage was reduced by amifostine.

Radioprotective Effect of Epigallocatechin-3-Gallate on Salivary Gland Dysfunction After Radioiodine Ablation in a Murine Model.

Objectives.Radioiodine (RI) therapy is known to subject cellular components of salivary glands (SG) to oxidative stress leading to SG dysfunction. However, the protective effects of antioxidants on RI-induced SG damage have not been well investigated. The authors investigated the morphometric and functional effects of epigallocatechin-3-gallate (EGCG) administered prior to RI therapy and compared this with the effects of amifostine (a well-known antioxidant) in a murine model of RI sialadenitis.Methods.Four-week-old female C57BL/6 mice (n=48) were divided into four groups; a normal control group, a RI-treated group (0.01 mCi/g mouse, orally), an EGCG and RI-treated group, and an amifostine and RI-treated group. Animals in these groups were divided into 3 subgroups and euthanized at 15, 30, and 90 days post-RI treatment. Salivary flow rates and lag times were measured, and morphologic and histologic examinations and TUNEL (terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling) assays were performed. Changes in salivary 99mTc pertechnetate uptake and excretion were followed by single-photon emission computed tomography.Results.Salivary flow rates and lag times to salivation in the EGCG or amifostine groups were better than in the RI-treated group. Histologic examinations of SGs in the EGCG or amifostine group showed more mucin-rich parenchyma and less periductal fibrosis than in the RI-treated group. Fewer apoptotic cells were observed in acini, ducts, and among endothelial cells in the EGCG or amifostine group than in the RI group. In addition, patterns of 99mTc pertechnetate excretion were quite different in the EGCG or amifostine group than in the RI group.Conclusion.EGCG supplementation before RI therapy could protect from RI-induced SG damage in a manner comparable to amifostine, and thus, offers a possible means of preventing SG damage by RI.

The effect of amifostine on lung ischaemia-reperfusion injury in rats.

Lung ischaemia-reperfusion injury (LIRI) frequently occurs after lung transplantation or cardiac surgery with cardiopulmonary bypass, thus increasing postoperative morbidity and mortality. As LIRI is associated with the release of reactive oxygen species and a subsequent inflammatory reaction, we tested whether amifostine, a thiol and free radical scavenger, has a beneficial effect on LIRI. A total number of 72 Wistar rats were subjected to LIRI with or without a single or double dose of amifostine (100 mg/kg, intraperitoneally). Experimental induction of LIRI was performed by clamping either the left lung hilum or the pulmonary artery alone for 60 min, followed by 90 min of reperfusion. Control groups consisted of LIRI and NaCl, a sham group and a no intervention group (baseline). At the end of the experiments, the left lung was analysed by quantitative RT-PCR of inflammatory marker gene expression, western blot of activated nuclear factor-κB (NF-κB) and light and electron microscopy. In placebo and amifostine groups, the expression levels of pro-inflammatory markers were increased significantly and to a similar extent independent of the type of ischaemia induction. In contrast, amifostine reduced the activation of NF-κB in comparison with placebo. This effect was present independent of the type of ischaemia or the application of a single or double dose of amifostine. However, oedema formation, blood-gas barrier damage and inflammatory reaction were similar in all amifostine or placebo LIRI groups. Despite a significant reduction in NF-κB activation, amifostine failed to decrease the inflammatory response and structural changes induced by LIRI in this experimental setting.

CCM-AMI, a Polyethylene Glycol Micelle with Amifostine, as an Acute Radiation Syndrome Protectant in C57BL/6 Mice.

Acute radiation syndrome results from radiation exposure, such as in accidental nuclear disasters. Safe and effective radioprotectants, mitigators, and treatment drugs must be developed as medical countermeasures against radiation exposure. Here, the authors evaluated CCM-Ami, a novel polyethylene glycol micelle encapsulated with amifostine, for its radioprotective properties after total-body irradiation from a 60Co source. Male C57BL/6 mice (6-8 wk old) were intravenously injected with 45 mg kg(-1) of CCM-Ami 90 min before exposure to 7.2 and 8.5 Gy irradiation at a dose rate of 0.04 Gy min(-1). Both survival benefit and hematopoietic protection were observed after prophylactic CCM-Ami administration when compared with the effects measured in excipient control and amifostine groups. Pharmacokinetic results showed that after the intravenous injection, the plasma concentration of WR-1065, the active form of amifostine, was higher in CCM-Ami-treated mice than in amifostine-treated mice. These findings suggest that CCM-Ami-mediated hematopoietic protection plays a key role in enhancing survival of mice exposed to radiation toxicity and thus indicate that CCM-Ami is a radioprotectant that can be used safely and effectively in nuclear disasters.

Inhibition of Radiation-Induced Oxidative Damage in the Lung Tissue: May Acetylsalicylic Acid Have a Positive Role?

The lung is relatively sensitive to irradiation. It is shown that acetylsalicylic acid (ASA) might reduce oxidative injury and that it has a place in protection from cancer. The aim of this study is to evaluate the potential radioprotective effects of ASA. Whole-body irradiation (6 Gy, single dose) was applied to the rats. Glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels in the lung tissue were measured. Control (C), Radiation (R), Radiation + ASA (R + ASA; received irradiation and 25 mg/kg of ASA intraperitoneally (i.p.)), and Radiation + Amifostine (R + WR-2721; received irradiation and 200 mg/kg of WR-2721 i.p.) groups were used. The MPO levels decreased statistically significantly in the group administered ASA. Histopathologically, a radioprotective effect of ASA was more evident in the R + ASA group. ASA is an agent which has not been used as a radioprotector in the clinic yet, and it is worth supporting with more advanced studies.

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.

UTL-5g Lowers Levels of TGF-β and TNF-α Elevated by Lung Irradiation and Does Not Affect Tumor-response to Irradiation

UTL-5g is a small-molecule TNF- inhibitor having chemoprotective and liver radioprotective effects. We investigated the effects of UTL-5g on lung irradiated mice and whether UTL-5g affects tumor responses to radiotherapy. C57BL/6 mice were individually treated with UTL-5g at 15, 30, and 60 mg/kg and amifostine (200 mg/kg) by i.p. injection 30 min prior to lung irradiation of 6 Gy (daily x 5). Two mice in the amifostine group died within 8 wks. At the first time point (8 wks), the plasma levels of TGF-β elevated by irradiation were significantly reduced by UTL-5g at 60 mg/kg (p 60 days after lung irradiation). The results indicate that UTL-5g may protect melanocytes against radiation-induced injury. Next, the effects of UTL-5g on tumor response were investigated in CD-1 nu/nu athymic nude mice bearing intramuscular A549 tumors (human non-small cell lung carcinoma) implanted in the right gastrocnemius muscle. Animals were treated with UTL-5g (30 mg/kg i.p.) 30 min prior to or after irradiation (5 Gy) daily for five days. The results showed that UTL-5g did not protect tumor from radiation damage. These observations suggest that UTL-5g may be lung radioprotective and thus, warranted further investigation.

Pulmonary toxicity in a rabbit model of stereotactic lung radiation therapy: Efficacy of a radioprotector

ABSTRACTThis study aimed to assess the efficacy of the radioprotector amifostine in limiting radiation toxicity in a rabbit model of lung stereotactic body radiation therapy (SBRT) by correlating contrast-enhanced magnetic resonance angiography (ce-MRA), computed tomography (CT), and helium-3 (He-3) magnetic resonance imaging (MRI) with histopathology. Multiple MRI techniques were tested to obtain complementing physiologic information. Thirteen rabbits received SBRT to the right lower lobe of the lung. Specifically, 4 received 3 × 11 Gray (Gy), 6 received 3 × 11 Gy and 50 mg/kg of amifostine pre-SRBT, and 3 received 3 × 7, 3 × 9, or 3 × 13 Gy. Imaging was performed at baseline and 4, 8, 12, and 16 weeks post-SBRT. Ce-MRA perfusion difference between lungs in the irradiated group at 16 weeks post-treatment was statistically significant (P = .04) whereas the difference in the irradiated + amifostine group was not (P = .30). Histologically observed low red blood cell (RBC) count and CT hypodensity suggests changes were primarily related to perfusion; however, structural changes, such as increased alveolar size, were also present. No changes in He-3 MRI lung ventilation were observed in either group. Although radiation-induced injury detected in rabbits as CT hypodensity contrasted with increased density observed in humans/rodents, the changes in ce-MRA and CT were still significantly reduced after the addition of amifostine to SBRT. Use of CT and selected MRI techniques helped to pinpoint primary physiologic changes.

Amifostine enhances the antioxidant and hepatoprotective effects of UW and HTK preservation solutions.

To investigate whether amifostine contributes to the antioxidant and cytoprotective effects of histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions. 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. 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. Here, we show that preoperative administration of a single dose of amifostine is sufficient to minimize the preservation damage in hepatic cells.

Amifostine Preserves Osteocyte Number and Osteoid Formation in Fracture Healing Following Radiotherapy

Radiation is known to decrease osteocyte count and function, leading to bone weakening. A treatment strategy to mitigate these consequences could have immense therapeutic ramifications. The authors previously reported significantly decreased osteocyte count and mineralization capacity in a rat model of fracture healing after radiotherapy. They hypothesized that amifostine (AMF) would preserve osteocyte number and function in this model. Thirty-six rats were divided into 3 groups: fracture, radiated fracture, and radiated fracture with AMF. Radiated groups underwent human-equivalent radiotherapy to the mandible before fixator placement and mandibular osteotomy. The AMF group received a subcutaneous injection before each dose of radiotherapy. After 40 days, mandibles were harvested for histologic processing. Quantification of osteocyte count (Oc), empty lacunae (EL), and osteoid ratio (osteoid volume [OV] to tissue volume [TV]) was performed and the results were compared using analysis of variance (P < .05). Radiated fractures showed significantly decreased Oc, increased EL, and a decreased capacity to produce new osteoid at the fracture site as measured with OV/TV compared with nonradiated fractures. In mandibles treated with AMF, these metrics were not statistically different than the control, indicating a preservation of osteocyte number and function. These results support the hypothesis that AMF preserves osteocyte number and function, thereby preventing the pernicious effects of radiotherapy on the cellular environment of fracture healing. Based on these findings, the authors encourage future investigation of this promising therapy for use in the prevention of pathologic fractures and osteoradionecrosis.