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International Journal of Molecular... Dec 2015Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and... (Review)
Review
Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.
Topics: Alpha-Globulins; Humans; Kidney; Oxidation-Reduction; Oxidative Stress; Protective Agents; Radiometry; Radionuclide Imaging; Receptors, Peptide
PubMed: 26694383
DOI: 10.3390/ijms161226234 -
Folia Neuropathologica 2020Amifostine is a cytoprotective compound that is beneficial in ischaemic stroke cases. However, the neuroprotective effect of amifostine on ischaemia/reperfusion...
Amifostine is a cytoprotective compound that is beneficial in ischaemic stroke cases. However, the neuroprotective effect of amifostine on ischaemia/reperfusion (I/R)-induced brain injury and its underlying mechanism are still poorly understood. Herein, we constructed an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury and an in vitro model of oxygen and glucose deprivation and reperfusion (OGD/R) injury. After administration of amifostine, we found significant improvements in neurological deficits, infarct size, and cerebral oedema. Moreover, amifostine alleviated histopathological alteration and increased the number of surviving neurons. Biochemical analysis showed that treatment with amifostine obviously improved the brain damage of MCAO/R mice, as manifested by a decrease in reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and an increase in superoxide dismutase (SOD) activity. Moreover, amifostine decreased the mitochondrial membrane potential (m) loss, and cytochrome c escaping to cytoplasm, but increased the ATP level. In vitro, amifostine also showed an antioxidant effect, which was reflected by the reduced ROS generation, decreased mitochondrial superoxide generation, increased total SOD, SOD1 (Cu/Zn SOD, cytoplasmic SOD), and SOD2 (mitochondrial SOD) activities, and decreased m loss. Furthermore, amifostine suppressed neuronal apoptosis, accompanied by the reduction of Bax, cleaved caspase-9, cleaved caspase-3, and Bcl-2 upregulation. Amifostine also reduced the expression of p-p38 (Thr 180/Tyr 182) in vivo and in vitro. In short, amifostine exhibits a protective effect on cerebral I/R damage through modulating p38-related oxidative stress, mitochondrial dysfunction, and apoptosis.
Topics: Amifostine; Animals; Antioxidants; Brain Ischemia; MAP Kinase Signaling System; Male; Mice, Inbred C57BL; Mitochondria; Neuroprotective Agents; Oxidative Stress; Reperfusion Injury
PubMed: 33480238
DOI: 10.5114/fn.2020.102436 -
BioRxiv : the Preprint Server For... Jul 2023During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the...
During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Following validation, we tested other reported radioprotective drugs, including, Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin, confirming that all drugs but NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified with mechanisms of action other than antioxidant activity. Hits were down-selected using EC values and pharmacokinetics and pharmacodynamics data from the PubChem database leading to testing of Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited equivalent radioprotection to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful discovery and validation of novel radioprotective drugs with nonantioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.
PubMed: 37503292
DOI: 10.1101/2023.07.12.548707 -
Scientific Reports Jun 2023Amifostine is a normal cell protection agent, not only used in the adjuvant therapy of lung cancer, ovarian cancer, breast cancer, nasopharyngeal cancer, bone tumor,...
Amifostine is a normal cell protection agent, not only used in the adjuvant therapy of lung cancer, ovarian cancer, breast cancer, nasopharyngeal cancer, bone tumor, digestive tract tumor, blood system tumor and other cancers in order to reduce the toxicity of chemotherapy drugs, and recent studies have reported that the drug can also reduce lung tissue damage in patients with pulmonary fibrosis, but its mechanism of action is not yet fully understood. In this study, we explored the potential therapeutic effects and molecular mechanisms of AMI on bleomycin (BLM)-induced pulmonary fibrosis in mice. A mouse model of pulmonary fibrosis was established using BLM. We then assessed histopathological changes, inflammatory factors, oxidative indicators, apoptosis, epithelial-mesenchymal transition, extracellular matrix changes, and levels of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway-related proteins in the BLM-treated mice to determine the effect of AMI treatment on these factors. BLM-treated mice had substantial lung inflammation and abnormal extracellular matrix deposition. Overall, treatment with AMI significantly improved BLM-induced lung injury and pulmonary fibrosis. More specifically, AMI alleviated BLM-induced oxidative stress, inflammation, alveolar cell apoptosis, epithelial-mesenchymal transition, and extracellular matrix deposition by regulating the PI3K/Akt/mTOR signaling pathway. This finding that AMI can alleviate pulmonary fibrosis in a mouse model by inhibiting activation of the PI3K/Akt/mTOR signaling pathway lays a foundation for potential future clinical application of this agent in patients with pulmonary fibrosis.
Topics: Animals; Mice; Pulmonary Fibrosis; Amifostine; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Nasopharyngeal Neoplasms; Bleomycin; Disease Models, Animal; Signal Transduction; TOR Serine-Threonine Kinases; Mammals
PubMed: 37380638
DOI: 10.1038/s41598-023-34060-8 -
Biochimica Et Biophysica Acta.... Jun 2019Agents capable of scavenging ROS have attracted attention recently because of their potential use as antioxidative agents. Amifostine, a ROS scavenger, has the potential...
Agents capable of scavenging ROS have attracted attention recently because of their potential use as antioxidative agents. Amifostine, a ROS scavenger, has the potential to be used as an antioxidant in therapeutic applications. In this study, the effect of amifostine on neutral zwitterionic dipalmitoylphosphatidylcholine (DPPC) and anionic dipalmitoylphosphatidylglycerol (DPPG) model membranes' structure and dynamics is aimed to be examined by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). Our results revealed that amifostine at concentrations used (1-24 mol%) does not induce any important alteration in the shape of phase transition curve and phase transition temperature in the DPPC and DPPG membranes. High concentrations of amifostine slightly increased the acyl chain flexibility of DPPC membranes in the liquid crystalline phase and DPPG membranes in the gel phase. A lessening in the dynamics of DPPC liposomes was observed for all concentrations of amifostine in both phases but slight dual effect was observed only in the gel phase as a decrease in dynamics at low concentrations and an increase at higher concentrations of amifostine in DPPG liposomes. Additionally, strong hydrogen bonding was observed for both CO and PO groups in case of DPPC and for PO groups in case of DPPG. Dehydration around the CO regions occurred in case of DPPG. Accordingly, amifostine is proposed to be interacting strongly with zwitterionic and negatively charged membrane head groups and glycerol backbone in all concentrations and because of this interaction it causes some changes in lipid order and dynamics especially at high concentrations.
Topics: 1,2-Dipalmitoylphosphatidylcholine; Amifostine; Antioxidants; Liposomes; Phosphatidylglycerols; Radiation-Protective Agents; Temperature
PubMed: 31028720
DOI: 10.1016/j.bbamem.2019.04.009 -
Scientific Reports Aug 2016The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on... (Randomized Controlled Trial)
Randomized Controlled Trial
The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption and of carbon dioxide emission in cancer patients receiving amifostine. Glucose levels significantly decreased and lactate levels increased in patient venous blood. Although amifostine in vitro did not inhibit the activity of the prolyl-hydroxylase PHD2, experiments with mouse liver showed that on a short timescale WR-1065 induced expression of the Hypoxia Inducible Factor HIF1α, lactate dehydrogenase LDH5, glucose transporter GLUT2, phosphorylated pyruvate dehydrogenase pPDH and PDH-kinase. This effect was confirmed on normal mouse NCTC hepatocytes, but not on hepatoma cells. A sharp reduction of acetyl-CoA and ATP levels in NCTC cells indicated reduced mitochondrial usage of pyruvate. Transient changes of mitochondrial membrane potential and reactive oxygen species ROS production were evident. Amifostine selectively protects NCTC cells against radiation, whilst HepG2 neoplastic cells are sensitized. The radiation protection was correlates with HIF levels. These findings shed new light on the mechanism of amifostine cytoprotection and encourage clinical research with this agent for the treatment of primary and metastatic liver cancer.
Topics: Adenosine Triphosphate; Amifostine; Animals; Basal Metabolism; Blood Glucose; Breast Neoplasms; Female; Glucose Transporter Type 2; Glycolysis; Hepatocytes; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Male; Membrane Potential, Mitochondrial; Mice, Inbred BALB C; Oxygen; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Radiation-Protective Agents
PubMed: 27507219
DOI: 10.1038/srep30986 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Mar 2023This study aimed to examine whether two different doses of dexamethasone (DXM), which is a corticosteroid, and amifostine (AMI), which reduces cumulative tissue toxicity...
BACKGROUND
This study aimed to examine whether two different doses of dexamethasone (DXM), which is a corticosteroid, and amifostine (AMI), which reduces cumulative tissue toxicity induced by cisplatin in advanced-stage cancer patients, have ameliorative effects on pathologic changes associated with cardiac contusion (CC) induced in rats.
METHODS
Forty-two Wistar albino rats were equally divided into six groups (n=7): C, CC, CC+AMI 400, CC+AMI 200, CC+AMI+DXM, and CC+DXM. Tomography images and electrocardiographic analyzes were performed, mean arterial pressure was measured from the carotid artery, and blood and tissue samples were obtained for histopathological and biochemical analyses after trauma-induced CC.
RESULTS
While the total oxidant status and disulfide parameters in the cardiac tissue and serum were significantly higher (p<0.05), the total antioxidant status, total thiol, and native thiol parameters were significantly lower (p<0.01) in rats with trauma-induced CC. The most frequently observed finding in the electrocardiography analyze was ST elevation.
CONCLUSION
According to evaluation based on histological, biochemical, and electrocardiographic examinations, we believe that only 400 mg/kg dose of AMI or DXM can be effective in the treatment of myocardial contusion in rats. Evaluation based on histological findings.
Topics: Rats; Animals; Rats, Wistar; Thoracic Injuries; Amifostine; Wounds, Nonpenetrating; Heart Injuries; Myocardial Contusions
PubMed: 36880625
DOI: 10.14744/tjtes.2023.84308 -
Human & Experimental Toxicology 2022This study aimed to elucidate the effects of amifostine (ethyol) (AM), a synthetic radioprotector, and red ginseng (RG), a natural radioprotective agent, against the...
This study aimed to elucidate the effects of amifostine (ethyol) (AM), a synthetic radioprotector, and red ginseng (RG), a natural radioprotective agent, against the toxic effect of ionizing radiation (IR) on kidney tissues through changes in biochemical and histopathological parameters in addition to contributions to the use of amifostine and RG in clinical studies Five groups were established: Group I (control, receiving only saline by gavage), Group II (IR only), and Group III (IR+AM, 200 mg/kg intraperitoneally (i.p.). Group IV (IR + RG, 200 mg/kg orally once a day for 4 weeks), and Group V (IR+RG+AM, 200 mg/kg orally once/day for 4 weeks before IR and 200 mg/kg AM administered (i.p.) 30 min before IR). All groups, except for the control group, were subject to 6-Gy whole-body IR in a single fraction. 24 h after irradiation, all animals were sacrificed under anesthesia. IR enhanced MDA, 8-OHdG, and caspase-3 expression while decreasing renal tissue GSH levels ( < .05). Significant numbers of necrotic tubules together with diffuse vacuolization in proximal and distal tubule epithelial cells were also observed. The examination also revealed substantial brush boundary loss in proximal tubules as well as relatively unusual glomerular structures. While GSH levels significantly increased in the AM, RG, and AM+RG groups, a decrease in KHDS, MDA, 8-OHdG, and caspase-3 expression was observed, compared to the group subject to IR only ( < .05). Therefore, reactive oxygen species-scavenging antioxidants may represent a promising treatment for avoiding kidney damage in patients receiving radiation.
Topics: Animals; Amifostine; Caspase 3; Kidney; Radiation, Ionizing; 8-Hydroxy-2'-Deoxyguanosine; Panax
PubMed: 36455263
DOI: 10.1177/09603271221143029 -
Virulence Jan 2020MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It...
BACKGROUND
MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It is very urgent to develop new antimicrobials to solve this problem.
OBJECTIVE
Idarubicin was profiled to assess its antimicrobial effects and , and the underlying mechanisms.
METHODS
We investigated the antimicrobial effects of idarubicin against MRSA by time-kill analysis. The antibiofilm efficacy of idarubicin was assessed by crystal violet and XTT staining, followed by laser confocal microscopy observation. The mechanisms underlying the antimicrobial effects were studied by transmission electron microscopy, all-atom molecular dynamic simulations, SYTOX staining, surface plasma resonance, and DNA gyrase inhibition assay. Further, we addressed the antimicrobial efficacy in wound and subcutaneous abscess infection .
RESULTS
Idarubicin kills MRSA cells by disrupting the lipid bilayers and interrupting the DNA topoisomerase IIA subunits, and idarubicin shows synergistic antimicrobial effects with fosfomycin. Through synergy with a single dose treatment fosfomycin and the addition of the cell protector amifostine, the cytotoxicity and cardiotoxicity of idarubicin were significantly reduced without affecting its antimicrobial effects. Idarubicin alone or in combination with fosfomycin exhibited considerable efficacy in a subcutaneous abscess mouse model of MRSA infection. In addition, idarubicin also showed a low probability of causing resistance and good postantibiotic effects.
CONCLUSIONS
Idarubicin and its analogs have the potential to become a new class of antimicrobials for the treatment of MRSA-related infections.
Topics: Animals; Anti-Bacterial Agents; Biofilms; Drug Repositioning; Drug Synergism; Female; Fosfomycin; Idarubicin; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Molecular Dynamics Simulation; Specific Pathogen-Free Organisms; Staphylococcal Skin Infections
PubMed: 32423280
DOI: 10.1080/21505594.2020.1770493 -
Journal of Cancer Research and... 2014
Topics: Amifostine; Creativity; Humans; Hyperthermia, Induced; Medical Oncology; Organizational Innovation; Radiation-Protective Agents
PubMed: 25579510
DOI: 10.4103/0973-1482.148859