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Molecular Pharmaceutics Nov 2023Amifostine (AMF, also known as WR-2721) is the only approved broad-spectrum small-molecule radiation protection agent that can combat hematopoietic damage caused by... (Review)
Review
Amifostine (AMF, also known as WR-2721) is the only approved broad-spectrum small-molecule radiation protection agent that can combat hematopoietic damage caused by ionizing radiation and is used as an antitumor adjuvant and cell protector in cancer chemotherapy and radiotherapy. Amifostine is usually injected intravenously before chemotherapy or radiotherapy and has been used in the treatment of head and neck cancer. However, the inconvenient intravenous administration and its toxic side effects such as hypotension have severely limited its further application in clinic. In order to reduce the toxic and side effects, scientists are trying to develop a variety of drug administration methods and are devoted to developing a wide application of amifostine in radiation protection. This paper reviews the research progress of amifostine for radiation protection in recent years, discusses its mechanism of action, clinical application, and other aspects, with focus on summarizing the most widely studied amifostine injection administration and drug delivery systems, and explored the correlation between various administrations and drug efficacies.
Topics: Humans; Amifostine; Radiation Protection; Radiation-Protective Agents; Administration, Intravenous; Adjuvants, Immunologic; Drug-Related Side Effects and Adverse Reactions
PubMed: 37747899
DOI: 10.1021/acs.molpharmaceut.3c00600 -
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 -
Cancer Biotherapy & Radiopharmaceuticals Oct 1999
Review
Topics: Amifostine; Animals; Clinical Trials as Topic; Humans; Neoplasms; Neoplasms, Experimental; Radiation-Protective Agents
PubMed: 10850317
DOI: 10.1089/cbr.1999.14.331 -
Asian Pacific Journal of Cancer... Sep 2022Amifostine 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...
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSION
Acute pericarditis was detected in all rats receiving radiotherapy. There was no positive effect of amifostine administration before radiotherapy on acute pericardial inflammation.
Topics: Amifostine; Animals; Antioxidants; Inflammation; Pericarditis; Radiation Injuries; Radiation-Protective Agents; Rats; Saline Solution
PubMed: 36172686
DOI: 10.31557/APJCP.2022.23.9.3209 -
The Oncologist Jun 2007After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been... (Review)
Review
After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been shown to specifically protect normal tissues from damage caused by radiation and chemotherapy. An inactive prodrug, amifostine is converted to an active thiol by dephosphorylation by alkaline phosphatase in the normal endothelium. The hypovascularity and acidity of the tumor environment and the differential expression of alkaline phosphatase in normal and neoplastic tissues contribute to its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free-radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug Administration has approved the i.v. use of amifostine to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Nonetheless, amifostine has potential applications in many other oncologic settings. Novel schedules and routes of administration are under investigation and may further simplify the use of amifostine, reduce any undesired effects, and considerably broaden its applications. This review summarizes the clinical experience with amifostine and provides insight into future clinical directions.
Topics: Amifostine; Humans; Mucositis; Neoplasms; Radiation-Protective Agents; Radiotherapy; Treatment Outcome; Xerostomia
PubMed: 17602063
DOI: 10.1634/theoncologist.12-6-738 -
Seminars in Oncology Dec 2003A large body of experimental evidence suggests that amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD) is a selective cytoprotector of normal tissues.... (Review)
Review
A large body of experimental evidence suggests that amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD) is a selective cytoprotector of normal tissues. Nevertheless, several experimental studies, most of which were conducted in the early 1980s, suggest that amifostine may protect tumor tissues, although to a much lower degree than its protective effect on normal tissues. Based on a critical literature review, we conclude that any experimental evidence suggesting tumor protection is weak. The effects of anesthesia and hypotension on normal and tumor tissue oxygenation status of animals, the consequences of such events on amifostine activity, and the impact of this complex situation on host immunity and radiotherapy efficacy in the experimental setting do not reliably simulate the clinical setting. Analyses of radiobiologic and histologic results of the Canine Sarcoma Study show that, if any conclusion is to be made, amifostine protected normal tissues and preserved (or even enhanced) the antitumor activity of radiotherapy. The Ormaplatin Study clearly showed a 10-fold decreased concentration of platinum in tumor compared with normal tissues, and does not therefore support evidence of lack of amifostine selectivity. Finally, not one clinical study suggests tumor protection with amifostine. On the contrary, the majority of clinical data strongly suggest that patients who receive amifostine with radiotherapy and/or chemotherapy do better than controls. Rather than organizing large-scale, randomized clinical trials to exclude tumor protection by amifostine, it seems more useful to design trials that would measure amifostine benefits in terms of improved quality of life, tumor control, and survival rates in patients being treated with standard or novel chemotherapy/radiotherapy regimens.
Topics: Amifostine; Animals; Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; Dogs; Drug Evaluation, Preclinical; Humans; Mercaptoethylamines; Models, Animal; Neoplasms; Organoplatinum Compounds; Radiation Injuries; Radiation-Protective Agents; Rats; Sarcoma
PubMed: 14727237
DOI: 10.1053/j.seminoncol.2003.11.014 -
Expert Opinion on Drug Safety Nov 2019: A radiation countermeasure that can be used prior to radiation exposure to protect the population from the harmful effects of radiation exposure remains a major unmet... (Review)
Review
: A radiation countermeasure that can be used prior to radiation exposure to protect the population from the harmful effects of radiation exposure remains a major unmet medical need and is recognized as an important area for research. Despite substantial advances in the research and development for finding nontoxic, safe, and effective prophylactic countermeasures for the acute radiation syndrome (ARS), no such agent has been approved by the United States Food and Drug Administration (FDA). : Despite the progress made to improve the effectiveness of amifostine as a radioprotector for ARS, none of the strategies have resolved the issue of its toxicity/side effects. Thus, the FDA has approved amifostine for limited clinical indications, but not for non-clinical uses. This article reviews recent strategies and progress that have been made to move forward this potentially useful countermeasure for ARS. : Although the recent investigations have been promising for fielding safe and effective radiation countermeasures, additional work is needed to improve and advance drug design and delivery strategies to get FDA approval for broadened, non-clinical use of amifostine during a radiological/nuclear scenario.
Topics: Acute Radiation Syndrome; Amifostine; Animals; Drug Approval; Drug Design; Humans; Radiation-Protective Agents; United States; United States Food and Drug Administration
PubMed: 31526195
DOI: 10.1080/14740338.2019.1666104 -
Expert Opinion on Pharmacotherapy Mar 2001Amifostine (Ethyoltrade mark, Alza Pharmaceuticals) is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[3-... (Review)
Review
Amifostine (Ethyoltrade mark, Alza Pharmaceuticals) is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[3- aminopropyl)amino]dihydrogen phosphate. It is a prodrug of free thiol (WR-1065) that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. Differences in the alkaline phosphatase concentration of normal versus tumour tissues can result in greater conversion of amifostine in normal tissues. Inside the cell, WR-1065 provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapy agents. Preclinical animal studies have demonstrated that the administration of amifostine protects against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine has been shown to protect a variety of animal species from lethal doses of radiation. Amifostine gives haematological protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin and salivary gland protection from radiotherapy. Multiple Phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine were found to be 740 - 910 mg/m(2) in single-dose regimens and 340 mg/m(2) in multiple-dose regimens. In radioprotection, doses are generally 200 - 350 mg/m(2). For all these characteristics, amifostine has been recently approved and suggested in ASCO clinical practice guidelines as a radioprotector for head and neck cancer treatment and supportive agent during cisplatin-based chemotherapy, in lymphomas and solid tumours. Moreover, its spectrum of possible applications is enlarging. As data have been provided indicating that amifostine stimulates haematopoiesis, it has been employed with intriguing results in the treatment of myelodysplastic syndromes (MDS).
Topics: Amifostine; Animals; Clinical Trials as Topic; Humans; Radiation-Protective Agents
PubMed: 11336600
DOI: 10.1517/14656566.2.3.479 -
Anti-cancer Drugs Mar 2002Amifostine (Ethyol), an inorganic thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues that provides cytoprotection against ionizing radiation... (Review)
Review
Amifostine (Ethyol), an inorganic thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues that provides cytoprotection against ionizing radiation and chemotherapeutic agents, thus preserving the efficacy of radiotherapy and chemotherapy. This review summarizes the preclinical data and clinical experience with amifostine, and provides insight into future clinical directions. Amifostine, an inactive pro-drug, is transformed to an active thiol after dephosphorylation by alkaline phosphatase found in the normal endothelium. The absence of alkaline phosphatase in the tumoral endothelium and stromal components, and the hypovascularity and acidity of the tumor environment, may explain its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. Intravenous administration of amifostine 740-900 mg/m(2) before chemotherapy and 250-350 mg/m(2) before each radiotherapy fraction are widely used regimens. The US Food and Drug Administration has approved the use of amifostine as a cytoprotector for cisplatin chemotherapy and for radiation-induced xerostomia. Ongoing trials are being conducted to determine the efficacy of amifostine in reducing radiation-induced mucositis and other toxicities. Novel schedules and routes of administration are under investigation, and may further simplify the use of amifostine and considerably broaden its applications.
Topics: Amifostine; Animals; Humans; Neoplasms; Radiation-Protective Agents
PubMed: 11984063
DOI: 10.1097/00001813-200203000-00001 -
European Journal of Cancer (Oxford,... 1996Amifostine (Ethyol) administered to cancer patients is rapidly cleared from plasma by a biphasic decay with an alpha half-life (T1/2 alpha) of 0.88 min and a T1/2 beta... (Review)
Review
Amifostine (Ethyol) administered to cancer patients is rapidly cleared from plasma by a biphasic decay with an alpha half-life (T1/2 alpha) of 0.88 min and a T1/2 beta of 8.8 min. The result is that more than 90% of the drug has disappeared from the plasma compartment 6 min after intravenous (i.v.) administration. Only approximately 1% of the dose appears in the ascites. Animal studies indicate that amifostine is primarily excreted in urine-approximately 6% of the dose is excreted in the urine as amifostine and its metabolites WR-1065 and disulphides-which means that a large percentage of the dose is taken up by the tissues. Maximal tissue concentrations of WR-1065 and the disulphides were obtained between 10 and 30 min after an intraperitoneal injection of amifostine in mice, with the lowest concentrations in tumour tissues. Because WR-1065 gives protection to normal tissues rather than rescue, the pharmacokinetic data indicate that amifostine must be given shortly before administration of the cytostatic drug or radiation from which protection is required. For these reasons, amifostine is given to patients as a 15-min i.v. infusion before cisplatin and carboplatin to protect against their dose-limiting toxicities. In some regimens carboplatin is combined with three doses of amifostine because of the high concentration of the active carboplatin species during the first 4 h after administration. When carboplatin was administered as a 15-min i.v. infusion of 400 mg/m2 and amifostine as a 15-min i.v. infusion of 740 mg/m2 just before and 2 and 4 h after carboplatin, the area under the plasma concentration-time curve for ultrafilterable platinum increased from 253 +/- 45 microM.h (n = 6) for carboplatin alone to 305 +/- 63 microM.h (n = 11) for carboplatin+three doses of amifostine. Experiments in nude mice bearing OVCAR-3 xenografts showed that amifostine, given once before cisplatin or three times in combination with carboplatin, did not affect the antitumour effect of these drugs. When amifostine was only given just before carboplatin, it even stimulated the antitumour effect of carboplatin significantly.
Topics: Amifostine; Animals; Antineoplastic Agents; Carboplatin; Cisplatin; DNA Adducts; Drug Administration Schedule; Drug Interactions; Female; Mice; Ovarian Neoplasms
PubMed: 8976819
DOI: 10.1016/s0959-8049(96)00332-2