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Oxidative Medicine and Cellular... 2017The present study was aimed at investigating the effect of amifostine on myocardial ischemia/reperfusion (I/R) injury of mice and H9c2 cells cultured with TBHP...
The present study was aimed at investigating the effect of amifostine on myocardial ischemia/reperfusion (I/R) injury of mice and H9c2 cells cultured with TBHP (tert-butyl hydroperoxide). The results showed that pretreatment with amifostine significantly attenuated cell apoptosis and death, accompanied by decreased reactive oxygen species (ROS) production and lower mitochondrial potential (ΔΨm). In vivo, amifostine pretreatment alleviated I/R injury and decreased myocardial apoptosis and infarct area, which was paralleled by increased superoxide dismutase (SOD) and reduced malondialdehyde (MDA) in myocardial tissues, increased Bcl2 expression, decreased Bax expression, lower cleaved caspase-3 level, fewer TUNEL positive cells, and fewer DHE-positive cells in heart. Our results indicate that amifostine pretreatment has a protective effect against myocardial I/R injury via scavenging ROS.
Topics: Amifostine; Animals; Apoptosis; Cell Survival; Cells, Cultured; Disease Models, Animal; Mice; Mitochondria; Myocardial Reperfusion Injury; Oxidative Stress; Pre-Exposure Prophylaxis; Radiation-Protective Agents
PubMed: 28392886
DOI: 10.1155/2017/4130824 -
Molecules (Basel, Switzerland) May 2017The goal of combined pharmacological approaches in the treatment of the acute radiation syndrome (ARS) is to obtain an effective therapy producing a minimum of... (Review)
Review
The goal of combined pharmacological approaches in the treatment of the acute radiation syndrome (ARS) is to obtain an effective therapy producing a minimum of undesirable side effects. This review summarizes important data from studies evaluating the efficacy of combining radioprotective agents developed for administration prior to irradiation and therapeutic agents administered in a post-irradiation treatment regimen. Many of the evaluated results show additivity, or even synergism, of the combined treatments in comparison with the effects of the individual component administrations. It can be deduced from these findings that the research in which combined treatments with radioprotectors/radiomitigators are explored, tested, and evaluated is well-founded. The requirement for studies highly emphasizing the need to minimize undesirable side effects of the radioprotective/radiomitigating therapies is stressed.
Topics: Acute Radiation Syndrome; Amifostine; Animals; Dinoprostone; Drug Administration Schedule; Drug Combinations; Drug Synergism; Granulocyte Colony-Stimulating Factor; Humans; Metformin; Misoprostol; Radiation Injuries, Experimental; Radiation-Protective Agents; Vitamin E
PubMed: 28534834
DOI: 10.3390/molecules22050834 -
Health Physics Jun 2015World events over the past decade have highlighted the threat of nuclear terrorism as well as an urgent need to develop radiation countermeasures for acute radiation... (Review)
Review
Medical Countermeasures for Radiation Exposure and Related Injuries: Characterization of Medicines, FDA-Approval Status and Inclusion into the Strategic National Stockpile.
World events over the past decade have highlighted the threat of nuclear terrorism as well as an urgent need to develop radiation countermeasures for acute radiation exposures and subsequent bodily injuries. An increased probability of radiological or nuclear incidents due to detonation of nuclear weapons by terrorists, sabotage of nuclear facilities, dispersal and exposure to radioactive materials, and accidents provides the basis for such enhanced radiation exposure risks for civilian populations. Although the search for suitable radiation countermeasures for radiation-associated injuries was initiated more than half a century ago, no safe and effective radiation countermeasure for the most severe of these injuries, namely acute radiation syndrome (ARS), has been approved by the United States Food and Drug Administration (FDA). The dearth of FDA-approved radiation countermeasures has prompted intensified research for a new generation of radiation countermeasures. In this communication, the authors have listed and reviewed the status of radiation countermeasures that are currently available for use, or those that might be used for exceptional nuclear/radiological contingencies, plus a limited few medicines that show early promise but still remain experimental in nature and unauthorized for human use by the FDA.
Topics: Amifostine; Androstenediol; Animals; Drug Approval; Granulocyte Colony-Stimulating Factor; Humans; Metalloporphyrins; Peptides; Radiation Injuries; Radiation-Protective Agents; Strategic Stockpile; United States; United States Food and Drug Administration
PubMed: 25905522
DOI: 10.1097/HP.0000000000000279 -
Current Pharmacology Reports Apr 2017To summarize recent evidence supporting the use of reactive carbonyl species scavengers in the prevention and treatment of disease.
PURPOSE OF THE REVIEW
To summarize recent evidence supporting the use of reactive carbonyl species scavengers in the prevention and treatment of disease.
RECENT FINDINGS
The newly developed 2-aminomethylphenol class of scavengers shows great promise in preclinical trials for a number of diverse conditions including neurodegenerative diseases and cardiovascular disease. In addition, new studies with the thiol-based and imidazole-based scavengers have found new applications outside of adjunctive therapy for chemotherapeutics.
SUMMARY
Reactive oxygen species (ROS) generated by cells and tissues act as signaling molecules and as cytotoxic agents to defend against pathogens, but ROS also cause collateral damage to vital cellular components. The polyunsaturated fatty acyl chains of phospholipids in the cell membranes are particularly vulnerable to damaging peroxidation by ROS. Evidence suggests that the breakdown of these peroxidized lipids to reactive carbonyls species plays a critical role in many chronic diseases. Antioxidants that abrogate ROS-induced formation of reactive carbonyl species also abrogate normal ROS signaling and thus exert both beneficial and adverse functional effects. The use of scavengers of reactive dicarbonyl species represent an alternative therapeutic strategy to potentially mitigate the adverse effects of ROS without abrogating normal signaling by ROS. In this review, we focus on three classes of reactive carbonyl species scavengers: thiol-based scavengers (2-mercaptoethanesulfonate and amifostine), imidazole-based scavengers (carnosine and its analogs), and 2-aminomethylphenols-based scavengers (pyridoxamine, 2-hydroxybenzylamine, and 5'--pentyl-pyridoxamine) that are either undergoing pre-clinical studies, advancing to clinical trials, or are already in clinical use.
PubMed: 28993795
DOI: 10.1007/s40495-017-0081-6 -
Oxidative Medicine and Cellular... 2021Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the...
Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.
Topics: Administration, Oral; Amifostine; Animals; Apoptosis; Cell Differentiation; Cell Proliferation; DNA; DNA Damage; Dose-Response Relationship, Radiation; Free Radical Scavengers; Histones; Intestine, Small; Male; Mice, Inbred C57BL; Mice, Inbred ICR; Radiation-Protective Agents; Rats, Sprague-Dawley; Regeneration; Signal Transduction; Survival Analysis; Time Factors; Toxicity Tests, Acute; Treatment Outcome; Whole-Body Irradiation; Mice; Rats
PubMed: 33688393
DOI: 10.1155/2021/6683836 -
Pharmaceutics Aug 2023Cerium oxide nanoparticles (CONPs) have a unique surface redox chemistry that appears to selectively protect normal tissues from radiation induced damage. Our prior...
Cerium oxide nanoparticles (CONPs) have a unique surface redox chemistry that appears to selectively protect normal tissues from radiation induced damage. Our prior research exploring the biocompatibility of polymer-coated CONPs found further study of poly-acrylic acid (PAA)-coated CONPs was warranted due to improved systemic biodistribution and rapid renal clearance. This work further explores PAA-CONPs' radioprotective efficacy and mechanism of action related to tumor microenvironment pH. An ex vivo TUNEL assay was used to measure PAA-CONPs' protection of the irradiated mouse colon in comparison to the established radioprotector amifostine. [F]FDG PET imaging of spontaneous colon tumors was utilized to determine the effects of PAA-CONPs on tumor radiation response. In vivo MRI and an ex vivo clonogenic assay were used to determine pH effects on PAA-CONPs' radioprotection in irradiated tumor-bearing mice. PAA-CONPs showed excellent radioprotective efficacy in the normal colon that was equivalent to uncoated CONPs and amifostine. [F]FDG PET imaging showed PAA-CONPs do not affect tumor response to radiation. Normalization of tumor pH allowed some radioprotection of tumors by PAA-CONPs, which may explain their lack of tumor radioprotection in the acidic tumor microenvironment. Overall, PAA-CONPs meet the criteria for clinical application as a radioprotective therapeutic agent and are an excellent candidate for further study.
PubMed: 37631358
DOI: 10.3390/pharmaceutics15082144 -
Iranian Journal of Pharmaceutical... 2015A rapid, sensitive and reproducible HPLC method was developed and validated for the analysis of amifostine (AMF) and/or its metabolite, WR-1065 in human plasma. The...
A rapid, sensitive and reproducible HPLC method was developed and validated for the analysis of amifostine (AMF) and/or its metabolite, WR-1065 in human plasma. The method involves the alkylation of free sulfydryl group with iodoacetic acid followed by derivatization of the drug and its metabolite with o-phthaldialdehyde (OPA) and UVdetection at 340 nm. The derivatized AMF and WR-1065 were eluted in less than 11 min, and in the case of the metabolite with no interferences from the endogenous plasma peaks. Cystein was used as the internal standard. Analysis was carried out on a Eurosphere Performance (RP-18e, 100 × 4.6 mm) analytical column. The mobile phase was a mixture of methanol and phosphate buffer 0.03 M pH = 2.7 at a ratio of 40: 60v/v, respectively, with a flow rate of 1.5 mLmin(-1). Limit of detection was 0.5 µgmL(-1). The method involved a simple extraction procedure for AMF and/or its metabolite and analytical recovery was 90 ± 0.9%.The calibration curve was linear over the concentration range of 1-200 µgmL(-1). The coefficients of variation for intra-day and inter-day assays were less than 10%.
PubMed: 26664371
DOI: No ID Found -
Bioactive Materials Sep 2024Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even...
Unnecessary exposure to ionizing radiation (IR) often causes acute and chronic oxidative damages to normal cells and organs, leading to serious physiological and even life-threatening consequences. Amifostine (AMF) is a validated radioprotectant extensively applied in radiation and chemotherapy medicine, but the short half-life limits its bioavailability and clinical applications, remaining as a great challenge to be addressed. DNA-assembled nanostructures especially the tetrahedral framework nucleic acids (tFNAs) are promising nanocarriers with preeminent biosafety, low biotoxicity, and high transport efficiency. The tFNAs also have a relative long-term maintenance for structural stability and excellent endocytosis capacity. We therefore synthesized a tFNA-based delivery system of AMF for multi-organ radioprotection (tFNAs@AMF, also termed nanosuit). By establishing the mice models of accidental total body irradiation (TBI) and radiotherapy model of Lewis lung cancer, we demonstrated that the nanosuit could shield normal cells from IR-induced DNA damage by regulating the molecular biomarkers of anti-apoptosis and anti-oxidative stress. In the accidental total body irradiation (TBI) mice model, the nanosuit pretreated mice exhibited satisfactory alteration of superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents, and functional recovery of hematopoietic system, reducing IR-induced pathological damages of multi-organ and safeguarding mice from lethal radiation. More importantly, the nanosuit showed a selective radioprotection of the normal organs without interferences of tumor control in the radiotherapy model of Lewis lung cancer. Based on a conveniently available DNA tetrahedron-based nanocarrier, this work presents a high-efficiency delivery system of AMF with the prolonged half-life and enhanced radioprotection for multi-organs. Such nanosuit pioneers a promising strategy with great clinical translation potential for radioactivity protection.
PubMed: 38808157
DOI: 10.1016/j.bioactmat.2024.05.017 -
Journal of Bone and Mineral Metabolism May 2015Despite its therapeutic role in head and neck cancer, radiation administration degrades the biomechanical properties of bone and can lead to pathologic fracture and...
Despite its therapeutic role in head and neck cancer, radiation administration degrades the biomechanical properties of bone and can lead to pathologic fracture and osteoradionecrosis. Our laboratories have previously demonstrated that prophylactic amifostine administration preserves the biomechanical properties of irradiated bone and that Raman spectroscopy accurately evaluates bone composition ex vivo. As such, we hypothesize that Raman spectroscopy can offer insight into the temporal and mechanical effects of both irradiation and amifostine administration on bone to potentially predict and even prevent radiation-induced injury. Male Sprague-Dawley rats (350-400 g) were randomized into control, radiation exposure (XRT), and amifostine pre-treatment/radiation exposure groups (AMF-XRT). Irradiated animals received fractionated 70 Gy radiation to the left hemi-mandible, while AMF-XRT animals received amifostine just prior to radiation. Hemi-mandibles were harvested at 18 weeks after radiation, analyzed via Raman spectroscopy, and compared with specimens previously harvested at 8 weeks after radiation. Mineral (ρ958) and collagen (ρ1665) depolarization ratios were significantly lower in XRT specimens than in AMF-XRT and control specimens at both 8 and 18 weeks. amifostine administration resulted in a full return of mineral and collagen depolarization ratios to normal levels at 18 weeks. Raman spectroscopy demonstrates radiation-induced damage to the chemical composition and ultrastructure of bone while amifostine prophylaxis results in a recovery towards normal, native mineral and collagen composition and orientation. These findings have the potential to impact on clinical evaluations and interventions by preventing or detecting radiation-induced injury in patients requiring radiotherapy as part of a treatment regimen.
Topics: Amifostine; Animals; Collagen; Male; Mandible; Osteoradionecrosis; Rats; Rats, Sprague-Dawley; Spectrum Analysis, Raman
PubMed: 25319554
DOI: 10.1007/s00774-014-0599-1 -
Endocrine Connections Oct 2017Amifostine is a potent scavenger of reactive oxygen species that is used for the salivary gland protection during therapy with radioactive iodine for thyroid cancer....
BACKGROUND
Amifostine is a potent scavenger of reactive oxygen species that is used for the salivary gland protection during therapy with radioactive iodine for thyroid cancer. There are no data on the potential effect of amifostine on thyroid cancer cells.
METHODS
We investigated the effects of the active form of amifostine (WR-1065) on the response of thyroid cancer cells to treatment with DNA-damaging agents. WR-1065 was examined in human thyroid cancer cell lines (FTC133, TPC1, BCPAP and C643) and embryonic fibroblast cells NIH3T3. DNA damage was induced by exposure to HO (0.1 mM), by treatment with the radiomimetic neocarzinostatin (NCS 250 ng/mL) and by γ-radiation (6 Gy). DNA damage, cell viability and apoptosis were examined.
RESULTS
We demonstrated the selective action of WR-1065 (0.1 mM), which prevented oxidative stress-induced DNA damage in fibroblasts, but did not protect thyroid cancer cells from DNA damage and apoptosis documented by caspase-3 and PARP cleavage after exposure to HO, NCS and γ-radiation. Prolonged exposure to WR-1065 (0.1 mM for 24 h) was toxic for thyroid cancer cells; this treatment decreased the number of viable cells by 8% in C643 cells, 47% in TPC cells, 92% in BCPAP cells and 82% in FTC 133 cells. The cytotoxic effects of WR-1065 were not associated with induction of apoptosis.
CONCLUSIONS
Our data show that amifostine has no protective effect on thyroid cancer cells against DNA-damaging agents and suggest that amifostine will not attenuate the efficacy of radioiodine treatment in patients with thyroid cancer.
PubMed: 28790138
DOI: 10.1530/EC-17-0138