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Oncology Reports 1999Patients receiving systemic cancer chemotherapy must often have their dose intensity of therapeutic agents reduced, because a broad range of organs are adversely... (Review)
Review
Patients receiving systemic cancer chemotherapy must often have their dose intensity of therapeutic agents reduced, because a broad range of organs are adversely affected. Therefore, research and the development of agents protecting the normal tissues from the toxicity of antineoplastic therapy, without reducing the antitumour efficacy, are very important. Amifostine, a prodrug that forms an activated free thiol, when dephosphorylated by alkaline phosphatase, appears selective in its entry in non-malignant cells, and exerts a protective effect from toxicity induced by chemo- or radiotherapy on normal tissues, through free radical scavenging, hydrogen donation and inhibition of DNA damage. Studies in vitro and experimental models have confirmed the protective properties of amifostine in normal cells. In clinical trials pretreatment with amifostine reduced the frequency of cyclophosphamide induced neutropenia and nephro-, oto- and neurotoxicity of platinum compounds. In some cases the use of amifostine have also potentiated the effects of several drugs, such as alkylating agents and, in recent studies, taxanes. The main potentially dose-limiting adverse effect is hypotension, that is often asymptomatic. Amifostine is thus usefully employed in order to obtain a better quality of life in patients receiving oncologic treatments.
Topics: Amifostine; Antineoplastic Combined Chemotherapy Protocols; Humans; Neoplasms; Radiation-Protective Agents; Radiotherapy
PubMed: 10523712
DOI: 10.3892/or.6.6.1357 -
Seminars in Oncology Aug 1996Administered prior to cytotoxic chemotherapy or radiation, the aminothiol amifostine provides broad-spectrum cytoprotection of various normal tissues without attenuating... (Review)
Review
Administered prior to cytotoxic chemotherapy or radiation, the aminothiol amifostine provides broad-spectrum cytoprotection of various normal tissues without attenuating antitumor response. The basis for the selectivity of action resides in the anabolism of amifostine at the normal tissue site by membrane-bound alkaline phosphatase. Dephosphorylation to the free thiol WR-1065 is followed by rapid uptake into normal tissues by a carrier-mediated facilitated diffusion process. In contrast, uptake into tumor tissues is slow to negligible. Pretreatment with amifostine provides protection of normal tissues from the cytotoxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes, and radiation. Additionally, the mutagenic and carcinogenic effects of these modalities are also attenuated. Preclinical studies show significant protection of marrow progenitor cells that give rise to the red blood cells, white blood cells, and platelets. Protection of kidneys and neural tissues from cisplatin toxicity has been shown, along with protection of the heart, intestinal crypt cells, and pulmonary tissues from chemotherapy and radiation, as well as vasculoconnective and musculoconnective tissue in an irradiated field. Comparative in vitro and in vivo studies using murine and human tumor xenografts show no attenuation of antitumor effects of these same therapies despite the protection of normal organs. The unique preclinical profile of amifostine serves as the basis for the clinical development program for this important new broad-spectrum cytoprotective agent.
Topics: Amifostine; Animals; Antineoplastic Agents; Cells; Combined Modality Therapy; Humans; Mercaptoethylamines; Neoplasms; Premedication
PubMed: 8783661
DOI: No ID Found -
European Journal of Cancer (Oxford,... 1996Cytoprotection utilising amifostine (Ethyol, WR-2721) is an evolving strategy to protect normal cells from the toxicity of chemotherapy. The dosing and administration... (Review)
Review
Cytoprotection utilising amifostine (Ethyol, WR-2721) is an evolving strategy to protect normal cells from the toxicity of chemotherapy. The dosing and administration guidelines are reviewed. The recommended dose of amifostine is 910 mg/m2 as a 15-min infusion prior to chemotherapy. Toxicity of this agent is moderate with hypotension and nausea/vomiting being observed in variable numbers of patients. Administration of amifostine with chemotherapy is simple and is associated with acceptable toxicity.
Topics: Amifostine; Antineoplastic Agents; Drug Administration Schedule; Humans; Hypotension
PubMed: 8976823
DOI: 10.1016/s0959-8049(96)00328-0 -
The Journal of Pharmacy and Pharmacology Jul 2008Amifostine (ethiofos, WR-2721) is an organic thiophosphate prodrug that serves as an antineoplastic adjunct and cytoprotective agent useful in cancer chemotherapy and... (Review)
Review
Amifostine (ethiofos, WR-2721) is an organic thiophosphate prodrug that serves as an antineoplastic adjunct and cytoprotective agent useful in cancer chemotherapy and radiotherapy. The selective protection of certain tissues of the body is believed to be due to higher alkaline phosphatase activity, higher pH and vascular permeation of normal tissues. Amifostine is conventionally administered intravenously before chemotherapy or radiotherapy. It is approved by the Food and Drug Administration (FDA) to reduce cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer. It was originally indicated to reduce the cumulative renal toxicity from cisplatin in non-small cell lung cancer although this indication was withdrawn in 2005. Amifostine is also FDA approved for patients with head and neck cancer to reduce the incidence of moderate to severe xerostomia in patients who are undergoing postoperative radiation treatment where the radiation port includes a substantial portion of the parotid glands. The potential of amifostine as a cytoprotective agent is unlikely to be fully realized if the method of administration is restricted to intravenous administration. Attempts have been made to develop non-invasive methods of delivery such as transdermal patches, pulmonary inhalers, and oral sustained-release microspheres. It is the goal of this article to explore non-intravenous routes of administration associated with better efficacy of the drug. This review will primarily focus on the variety of more recently studied (2002 and later) alternative modes for amifostine administration, including subcutaneous, intrarectal and oral routes.
Topics: Administration, Oral; Administration, Rectal; Amifostine; Animals; Biological Availability; Cytoprotection; Humans; Injections, Subcutaneous; Radiation-Protective Agents
PubMed: 18549666
DOI: 10.1211/jpp.60.7.0001 -
Life Sciences Jun 2022Radiotherapy of thoracic neoplasms and accidental radiation exposure often results in pneumonitis and fibrosis of lungs. Here, we investigated the potential of...
BACKGROUND
Radiotherapy of thoracic neoplasms and accidental radiation exposure often results in pneumonitis and fibrosis of lungs. Here, we investigated the potential of amifostine analogs: DRDE-07, DRDE-30, and DRDE-35, in alleviating radiation-induced lung damage.
METHODS
C57BL/6 mice were exposed to 13.5 Gy thoracic irradiation, 30 min after intraperitoneal administration of the analogs, and assessed for modulation of the pathological response at 12 and 24 weeks.
KEY FINDINGS
DRDE-07, DRDE-30 and DRDE-35 increased the survival of irradiated mice from 20% to 30%, 80% and 70% respectively. Reduced parenchymal opacity (X-ray CT) in the lungs of DRDE-30 pre-treated mice corroborated well with the significant decrease in Ashcroft score (p < 0.01). Two-fold increase in SOD and catalase activities (p < 0.05), coupled with a 50% increase in GSH content and a 60% decrease in MDA content (p < 0.05) suggested restoration of the antioxidant defence system. A 20% to 40% decrease in radiation-induced apoptotic and mitotic death in the lung tissue (micronuclei: p < 0.01), resulted in attenuated lung and vascular permeability (FITC-Dextran leakage) by 50% (p < 0.01), and a commensurate reduction (~50%) in leukocyte infiltration in the injured tissue (p < 0.05). DRDE-30 abrogated the activation of pro-inflammatory NF-κB and p38/MAPK signaling cascades, suppressing the release of pro-inflammatory cytokines (IL-1β: p < 0.05; TNF-α: p < 0.05; IL-6: p < 0.05) and up-regulation of CAMs on the endothelial cell surface. Reduction in hydroxyproline content (p < 0.01) and collagen suggested inhibition of lung fibrosis which was associated with attenuation of TGF-β/Smad pathway-mediated-EMT.
CONCLUSION
DRDE-30 could be a potential prophylactic agent against radiation-induced lung injury.
Topics: Amifostine; Animals; Inflammation; Lung; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Radiation Injuries
PubMed: 35367468
DOI: 10.1016/j.lfs.2022.120518 -
Seminars in Oncology Apr 1999Recent interest has focused on the use of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) as a possible multiorgan... (Review)
Review
Recent interest has focused on the use of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) as a possible multiorgan combined-modality protector. Amifostine has been shown to selectively protect normal tissues from the cytotoxic and mutagenic effects of alkylating and platinum-based chemotherapy and ionizing radiation. There are a number of approaches to ameliorating therapy-related toxicities, including the use of individual agents that target specific toxicities. However, amifostine is unique in that it possesses a broad range of tissue-protective effects. Amifostine has been studied in clinical trials comprising patients with lung cancer, head and neck cancer, and cancer of the cervix. Results of these trials show that amifostine can be safely administered to patients receiving chemotherapy and radiation therapy. These trials also demonstrate that amifostine has the potential to be a broad-spectrum cytoprotectant of normal tissues from the toxicities of radiation, as well as certain forms of chemotherapy. The selective cytoprotective effects of amifostine allow for the use of higher doses of cytotoxic therapy. Theoretically, this could improve therapeutic outcome in patients with cancer.
Topics: Amifostine; Clinical Trials as Topic; Combined Modality Therapy; Cytoprotection; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Neoplasms; Protective Agents; Uterine Cervical Neoplasms
PubMed: 10348267
DOI: No ID Found -
Biotechnic & Histochemistry : Official... Apr 2022The 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...
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.
Topics: Amifostine; Animals; In Situ Nick-End Labeling; Male; Radiation-Protective Agents; Rats; Rats, Wistar; Testis
PubMed: 34058938
DOI: 10.1080/10520295.2021.1933178 -
Seminars in Oncology Dec 2002Early studies of amifostine suggested a reduced frequency of nausea/vomiting and hypotension when the drug was given via shorter-duration, intravenous infusions. Data... (Review)
Review
Early studies of amifostine suggested a reduced frequency of nausea/vomiting and hypotension when the drug was given via shorter-duration, intravenous infusions. Data from subsequent clinical evaluations in the radioprotectant and cytoprotectant settings have supported this observation. Recent findings indicate that amifostine given preradiotherapy by rapid intravenous push (10 seconds) and prechemotherapy over 3 to 5 minutes is associated with reduced toxicity and improved tolerability without apparent loss of protective effects. In addition to reducing duration of infusion, steps that should be taken to improve amifostine tolerability include adequate pretreatment hydration, individualized antiemetic prophylaxis, and maintaining the patient in a supine or reclining position during and after amifostine treatment. Subcutaneous dosing is currently being assessed with the aim of improving ease of administration and potentially further improving tolerability. Semin Oncol 29 (suppl 19):9-13.
Topics: Amifostine; Antineoplastic Agents; Clinical Trials as Topic; Cytoprotection; Humans; Infusions, Intravenous; Injections, Subcutaneous; Neoplasms; Radiation Injuries; Radiation-Protective Agents; Radiotherapy
PubMed: 12577237
DOI: 10.1053/sonc.2002.37358 -
Haematologica Nov 1999Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihydrogen phosphate. It is a pro-drug of... (Review)
Review
BACKGROUND AND OBJECTIVE
Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihydrogen phosphate. It is a pro-drug of free thiol 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. In fact, pretreatment with amifostine was well tolerated and reduced the cumulative hematologic, renal and neurological toxicity associated with cisplatin, cyclophosphamide and vinblastine therapy of advanced and metastatic solid tumors. The objective of this review is to focus the importance of amifostine as a myeloprotective and cytoprotective drug during treatment with chemotherapeutics, presenting the most recent results, and to discuss the application of amifostine in the therapy of myelodysplastic syndromes.
EVIDENCE AND INFORMATION SOURCES
The material analyzed in this study includes data published or under publication by the authors as full papers or clinical protocols. Articles and abstracts published in Journals covered by Medline constitute the other source of information.
STATE OF THE ART AND PERSPECTIVES
Amifostine, formerly known as WR-2721, is an organic thiophosphate that was developed to protect normal tissues selectively against the toxicities of chemotherapy and radiation. Amifostine is a pro-drug that is dephosphorylated at the tissue site to its active metabolite by alkaline phosphatase. Differences in the alkaline phosphatase concentrations of normal versus tumor tissues can result in greater conversion of amifostine in normal tissues. Once inside the cell the free thiol 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 chemotherapies. Preclinical animal studies demonstrated that the administration of amifostine protected 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 was shown to protect a variety of animal species from lethal doses of radiation. Studies in tumor-bearing animals demonstrated that the administration of amifostine results in cytoprotection without loss of antitumor activity. Multiple phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine resulted to be 740-910 mg/m(2) in a single dose regimen, and 340 mg/m(2) in a multiple dose regimen. Amifostine afforded not only hematologic protection, but also other organ protection from cytotoxic agents such as nephrotoxicity, mucositis and peripheral neuropathy from cisplatin. Many studies have been performed to investigate cytoprotective efficacy of amifostine. In brief, amifostine gives hematologic protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin, and salivary gland from radiotherapy. In phase I/II studies these properties have been confirmed, together with a generally good tolerability of the drug, hypotension being the most common side effect. It has been observed that amifostine possibly enhances the anti-tumor effect of carboplatin, nitrogen mustard, melphalan, and cisplatin combined with 5-FU or vinblastine. For all these characteristics, amifostine is at present broadly used as supportive treatment during chemotherapy, in lymphomas and solid tumors, and its spec
Topics: Amifostine; Animals; Antineoplastic Agents; Hematologic Neoplasms; Humans; Neutropenia; Radiation-Protective Agents; Thrombocytopenia
PubMed: 10553165
DOI: No ID Found -
Expert Opinion on Drug Metabolism &... Oct 2008Radiation toxicity is an important problem that limits treatment intensity and adversely affects patients' quality of life. Amifostine is a cytoprotector that can reduce... (Comparative Study)
Comparative Study Review
BACKGROUND
Radiation toxicity is an important problem that limits treatment intensity and adversely affects patients' quality of life. Amifostine is a cytoprotector that can reduce toxicity and potentially improve the therapeutic ratio of radiotherapy.
OBJECTIVE
To discuss the role of amifostine in modern radiotherapy and compare and contrast with alternative approaches to reducing radiation toxicity.
METHODS
We conducted a literature search through Medline to identify randomized clinical trials pertaining to keyword 'amifostine'. We also consulted reviews, book chapters and selected articles regarding amifostine and normal tissue protection.
RESULTS/CONCLUSION
Amifostine is an effective normal tissue protector with level I evidence supporting its use in head and neck and gynecologic cancers but studies in other disease sites, although promising, are inconclusive. Further study is needed to demonstrate conclusively the benefits of wider amifostine use.
Topics: Amifostine; Female; Genital Neoplasms, Female; Head and Neck Neoplasms; Humans; Neoplasms; Radiation Injuries; Radiation-Protective Agents; Randomized Controlled Trials as Topic
PubMed: 18798703
DOI: 10.1517/17425255.4.10.1341