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Mini Reviews in Medicinal Chemistry 2020The thiol (-SH) functional group is found in a number of drug compounds and confers a unique combination of useful properties. Thiol-containing drugs can reduce radicals... (Review)
Review
The thiol (-SH) functional group is found in a number of drug compounds and confers a unique combination of useful properties. Thiol-containing drugs can reduce radicals and other toxic electrophiles, restore cellular thiol pools, and form stable complexes with heavy metals such as lead, arsenic, and copper. Thus, thiols can treat a variety of conditions by serving as radical scavengers, GSH prodrugs, or metal chelators. Many of the compounds discussed here have been in use for decades, yet continued exploration of their properties has yielded new understanding in recent years, which can be used to optimize their clinical application and provide insights into the development of new treatments. The purpose of this narrative review is to highlight the biochemistry of currently used thiol drugs within the context of developments reported in the last five years. More specifically, this review focuses on thiol drugs that represent the standard of care for their associated conditions, including N-acetylcysteine, 2,3-meso-dimercaptosuccinic acid, British anti-Lewisite, D-penicillamine, amifostine, and others. Reports of novel dosing regimens, delivery strategies, and clinical applications for these compounds were examined with an eye toward emerging approaches to address a wide range of medical conditions in the future.
Topics: Animals; Humans; Molecular Structure; Oxidative Stress; Sulfhydryl Compounds
PubMed: 31746294
DOI: 10.2174/1389557519666191119144100 -
Current Opinion in Oncology May 2015Oral mucositis remains a frequent debilitating toxicity associated with drug and radiation regimens used to treat cancer. This review highlights the recent understanding... (Review)
Review
PURPOSE OF REVIEW
Oral mucositis remains a frequent debilitating toxicity associated with drug and radiation regimens used to treat cancer. This review highlights the recent understanding of the biological basis, risk factors for, and management for oral mucositis.
RECENT FINDINGS
Prevalence and incidence data for mucositis are inconsistent and often underreported. The pathogenesis of mucositis encompasses a sequence of biological events possibly influenced by the oral microbiome and environment. Despite its frequency and severity, there is currently no effective treatment available for the majority of patients at risk. However, with the better understanding of the pathogenesis of mucositis a number of new drugs and biological agents are under investigation. Genome-wide risk prediction tools will allow the identification of patients at risk of developing mucositis.
SUMMARY
Oral mucositis is a common complication of cancer treatment that may negatively impact the patient's cancer treatment outcome. Despite its frequency and consequences, the lack of effective interventions has frustrated patients and caregivers. Fortunately, a broad range of mechanistically targeted compounds are being developed.
Topics: Amifostine; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Fibroblast Growth Factor 7; Humans; Neoplasms; Post-Exposure Prophylaxis; Quality of Life; Radiation-Protective Agents; Radiotherapy; Risk Factors; Stomatitis
PubMed: 25774860
DOI: 10.1097/CCO.0000000000000180 -
Oncology 2020Radiation therapy is a cornerstone of the therapeutic modalities used in modern oncology. However, it is sometimes limited in its ability to achieve optimal tumor... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Radiation therapy is a cornerstone of the therapeutic modalities used in modern oncology. However, it is sometimes limited in its ability to achieve optimal tumor control by radiation-induced normal tissue toxicity. In delivering radiation therapy, a balance must be achieved between maximizing the dose to the tumor and minimizing any injury to the normal tissues. Amifostine was the first Food and Drug Administration (FDA)-approved clinical radiation protector intended to reduce the impact of radiation on normal tissue, lessening its toxicity and potentially allowing for increased tumor dose/control. Despite being FDA-approved almost 20 years ago, Amifostine has yet to achieve widespread clinical use.
SUMMARY
A thorough review of Amifostine's development, mechanism of action, and current clinical status were conducted. A brief history of Amifostine is given, from its development at Walter Reid Institute of Research to its approval for clinical use. The mechanism of action of Amifostine is explored. The results of a complete literature review of all prospective randomized trials to date involving the use of Amifostine in radiation therapy are presented. The results are arranged by treatment site and salient findings discussed. Side effects and complications to consider in using Amifostine are reviewed. Key Messages: Amifostine has been explored as a radiation protectant in most radiation treatment sites. Studies have demonstrated efficacy of Amifostine in all treatment sites reviewed, but results are heterogeneous. The heterogeneity of studies looking at Amifostine as a clinical radiation protectant has precluded a definitive answer on its efficacy. Complicating its clinical use is its toxicity and delivery requirements. Amifostine has largely fallen out of use with the advent of intensity modulated radiation therapy (IMRT). However, side effects with IMRT remain a challenge and concern. The use of Amifostine in the IMRT era has been poorly explored and is worthy of future study.
Topics: Amifostine; Clinical Trials as Topic; Cytoprotection; Disease Management; Humans; Neoplasms; Organ Specificity; Radiation-Protective Agents; Treatment Outcome
PubMed: 31846959
DOI: 10.1159/000502979 -
Strahlentherapie Und Onkologie : Organ... Aug 2014Improvements of radiotherapy in combination with surgery and systemic therapy have resulted in increased survival rates of tumor patients. However, radiation-induced... (Comparative Study)
Comparative Study Review
Improvements of radiotherapy in combination with surgery and systemic therapy have resulted in increased survival rates of tumor patients. However, radiation-induced normal tissue toxicity is still dose limiting. Several strategies have been pursued with the goal to develop substances which may prevent or reduce damage to normal tissue. Drugs applied before radiotherapy are called radioprotectors; those given after radiotherapy to reduce long-term effects are radiomitigators. Despite more than 50 years of research, until now only two substances, amifostine and palifermin, have overcome all obstacles of clinical approval and are applied during radiotherapy of head and neck cancer or total body irradiation, respectively. However, better understanding of the cellular pathways involved in radiation response has allowed the development of several highly promising drugs functioning as scavengers of reactive oxygen species or targeting specific molecules involved in regulation of cell death pathways or cell cycle arrest. The present review describes the major targets for radioprotectors or radiomitigators currently tested in clinical trials.
Topics: Amifostine; Cell Survival; Clinical Trials as Topic; DNA Damage; Dose Fractionation, Radiation; Fibroblast Growth Factor 7; Free Radical Scavengers; Humans; Linear Energy Transfer; Otorhinolaryngologic Neoplasms; Radiation Injuries; Radiation-Protective Agents; Reactive Oxygen Species; Tumor Cells, Cultured; Whole-Body Irradiation
PubMed: 24638269
DOI: 10.1007/s00066-014-0637-x -
Vox Sanguinis Apr 2022Management of refractory immune thrombocytopaenia (ITP) can be challenging. Amifostine, a thiophosphate prodrug, induces megakaryocyte maturation. In 2010, Fan et al....
BACKGROUND AND OBJECTIVES
Management of refractory immune thrombocytopaenia (ITP) can be challenging. Amifostine, a thiophosphate prodrug, induces megakaryocyte maturation. In 2010, Fan et al. published results for 21 Chinese splenectomized patients, aged 13-92, with steroid-refractory ITP. Nineteen patients (15 patients aged >18 years) achieved remission 2 months post-amifostine. This is the first publication utilizing amifostine and rituximab in refractory ITP.
MATERIALS AND METHODS
At the Cairns Hospital in Australia, we identified five patients treated with amifostine and rituximab for refractory ITP. Amifostine IV 400 mg once daily was administered 5 days/week for 5 weeks as tolerated. Rituximab was administered concurrently with/preceding amifostine based on clinician preference. Data were obtained through medical records and follow-up serology up to 5 years post-amifostine was available.
RESULTS
Three cases demonstrated durable responses up to 5 years' follow-up. One patient initially achieved remission but relapsed 1-year post-amifostine. One patient who did not have a splenectomy prior to amifostine did not respond.
CONCLUSION
Three out of five patients achieved durable responses with amifostine and rituximab. Although there is confounding by rituximab, given its established low durable response rate, it is likely that the excellent long-term responses achieved were a result of amifostine. Clinical trials with larger patient cohorts and further investigation are required to confirm the efficacy and mechanism of amifostine in ITP.
Topics: Amifostine; Humans; Purpura, Thrombocytopenic, Idiopathic; Retrospective Studies; Rituximab; Splenectomy; Treatment Outcome
PubMed: 34939200
DOI: 10.1111/vox.13226 -
Anti-cancer Agents in Medicinal... 2023The side effects of ionising radiation include skin changes, dry mouth, hair loss, low blood count, and the mutagenic effect on normal cells when utilized in... (Review)
Review
BACKGROUND
The side effects of ionising radiation include skin changes, dry mouth, hair loss, low blood count, and the mutagenic effect on normal cells when utilized in radiotherapy for cancer treatment. These radiations can cause damage to the cell membrane, lipids, proteins, and DNA and generate free radicals. Evidence reports stated that radiotherapy accounts for 17-19% of secondary malignancies, labelling this treatment option a double-edged sword.
OBJECTIVE
Radioprotective molecules are used for mitigating radiotherapy's side effects. These agents show free radical scavenging, antioxidant, collagen synthesis inhibition, protease inhibition, immune stimulation, increased cytokine production, electron transfer, and toxicity reduction properties. The most frequently used amifostine has an array of cancer applications, showing multitarget action as nephroprotective to cisplatin and reducing the chances of xerostomia. Many other agents, such as metformin, edaravone, mercaptopropionylglycine, in specific diseases, such as diabetes, cerebral infarction, cystinuria, have shown radioprotective action. This article will discuss potentially repurposed radioprotectors that can be used in the clinical setting, along with a brief discussion on specific synthetic agents like amifostine and PrC-210.
METHODS
Rigorous literature search using various electronic databases, such as PubMed, ScienceDirect, Scopus, EMBASE, Bentham Science, Cochrane Library, etc., was made. Peer-review research and review papers were selected, studied, reviewed, and analysed.
CONCLUSION
Safety and risk-free treatment can be guaranteed with the repurposed agents. Agents like metformin, captopril, nifedipine, simvastatin, and various others have shown potent radioprotective action in various studies. This review compiled repurposed synthetic radioprotective agents.
Topics: Humans; Radiation-Protective Agents; Amifostine; Neoplasms
PubMed: 35379128
DOI: 10.2174/1871520622666220404090049 -
Current Opinion in Supportive and... Jun 2018Gastrointestinal mucositis is a frequent side effect of systemic anticancer treatment and radiotherapy. The occurrence endangers body resources by decreasing food intake... (Review)
Review
PURPOSE OF REVIEW
Gastrointestinal mucositis is a frequent side effect of systemic anticancer treatment and radiotherapy. The occurrence endangers body resources by decreasing food intake and absorption. This review highlights new developments in treatment and prevention.
RECENT FINDINGS
Recent clinical practice guidelines recommend supplying adequate amounts of energy and nutrients to cancer patients undergoing anticancer treatments. This requires repeated screening for risk of malnutrition and in at-risk patients, assessment of food intake and nutritional status, followed by nutritional interventions targeted at individual deficiencies and tolerance to oral, enteral or parenteral feeding. Recent preclinical data report beneficial effects of stimulating the sensor for cell damage signals TRPA1, blocking histamine H2 receptors or supplying probiotics. In a recent clinical trial, amifostine reduced gastrointestinal symptoms and was well tolerated. Probiotics are studied in ongoing clinical trials and glucagon-like peptide 2 analogues are considered for future trials. Due to limited options available today, it has been suggested to also consider several plant-based complementary therapies.
SUMMARY
Although options for prevention and treatment of chemotherapy or radiotherapy-induced gastrointestinal mucositis today are still limited, inadequate energy and nutrient intake should trigger nutritional interventions, including counselling, oral nutritional supplements, tube feeding and parenteral nutrition. To prevent gastrointestinal mucositis, several new agents have shown promising results in preclinical trials.
Topics: Animals; Body Mass Index; Counseling; Histamine H2 Antagonists; Humans; Malnutrition; Mucositis; Neoplasms; Nutrition Assessment; Nutritional Support; Palliative Care; Parenteral Nutrition; Practice Guidelines as Topic; Probiotics; TRPA1 Cation Channel; Weight Loss
PubMed: 29608464
DOI: 10.1097/SPC.0000000000000345 -
International Journal of Preventive... 2017Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment... (Review)
Review
Children with cancer treated with cytotoxic drugs are frequently at risk of developing renal dysfunction. The cytotoxic drugs that are widely used for cancer treatment in children are cisplatin (CPL), ifosfamide (IFO), carboplatin, and methotrexate (MTX). Mechanisms of anticancer drug-induced renal disorders are different and include acute kidney injury (AKI), tubulointerstitial disease, vascular damage, hemolytic uremic syndrome (HUS), and intrarenal obstruction. CPL nephrotoxicity is dose-related and is often demonstrated with hypomagnesemia, hypokalemia, and impaired renal function with rising serum creatinine and blood urea nitrogen levels. CPL, mitomycin C, and gemcitabine treatment cause vascular injury and HUS. High-dose IFO, streptozocin, and azacitidine cause renal tubular dysfunction manifested by Fanconi syndrome, rickets, and osteomalacia. AKI is a common adverse effect of MTX, interferon-alpha, and nitrosourea compound treatment. These strategies to reduce the cytotoxic drug-induced nephrotoxicity should include adequate hydration, forced diuresis, and urinary alkalization. Amifostine, sodium thiosulfate, and diethyldithiocarbamate provide protection against CPL-induced renal toxicity.
PubMed: 29114374
DOI: 10.4103/ijpvm.IJPVM_40_17 -
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 -
Oxidative Medicine and Cellular... 2016Cytoprotectant amifostine attenuates radiation-induced oxidative injury by increasing intracellular manganese superoxide dismutase (SOD2) in peripheral tissue. However,...
BACKGROUND
Cytoprotectant amifostine attenuates radiation-induced oxidative injury by increasing intracellular manganese superoxide dismutase (SOD2) in peripheral tissue. However, whether amifostine could protect neuronal cells against oxidative injury has not been reported. The purpose of this study is to explore the protection of amifostine in PC12 cells.
METHODS
PC12 cells exposed to glutamate were used to mimic neuronal oxidative injury. SOD assay kit was taken to evaluate intracellular Cu/Zn SOD (SOD1) and SOD2 activities; western blot analysis and immunofluorescence staining were performed to investigate SOD2 protein expression; MTT, lactate dehydrogenase (LDH), release and cell morphology were used to evaluate cell injury degree, and apoptotic rate and cleaved caspase-3 expression were taken to assess apoptosis; mitochondrial superoxide production, intracellular reactive oxygen species (ROS), and glutathione (GSH) and catalase (CAT) levels were evaluated by reagent kits.
RESULTS
Amifostine increased SOD2 activity and expression, decreased cell injury and apoptosis, reduced mitochondrial superoxide production and intracellular ROS generation, and restored intracellular GSH and CAT levels in PC12 cells exposed to glutamate. SOD2-siRNA, however, significantly reversed the amifostine-induced cytoprotective and antioxidative actions.
CONCLUSION
SOD2 mediates amifostine-induced protection in PC12 cells exposed to glutamate.
Topics: Amifostine; Animals; Apoptosis; Catalase; Glutamic Acid; Glutathione; Intracellular Space; Mitochondria; Models, Biological; Neuroprotection; PC12 Cells; RNA, Small Interfering; Rats; Reactive Oxygen Species; Superoxide Dismutase; Superoxides; Up-Regulation
PubMed: 26770652
DOI: 10.1155/2016/4202437