Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aminothiol, amifostine (Ethyol; U.S. Bioscience, West Conshohocken, PA), is a cytoprotective agent that ameliorates the toxicities of anticancer therapy. In vitro, amifostine promotes the formation and survival of primitive hematopoietic progenitors derived from myelodysplastic bone marrow (BM) specimens. To evaluate the hematological effects of amifostine, 18 patients with myelodysplastic syndrome (MDS) and one or more refractory cytopenias received treatment with amifostine in a Phase I/II study. Four cohorts received intravenous treatment with 100, 200, or 400 mg/m2 amifostine three times a week, or 740 mg/m2 weekly for three consecutive weeks followed by 2 weeks observation. Nonresponding patients received a second course of therapy at the next higher dose level depending upon drug tolerance. Bone marrow (BM) progenitor growth was assessed before treatment and after day 21. Diagnoses included refractory anemia (7), refractory anemia with ringed sideroblasts (5), refractory anemia with excess blasts (RAEB) (4), and RAEB-in transformation (RAEB-t) (2). Single- or multi-lineage hematologic responses occurred in 15 patients (83%) treated with the three-times-a-week dose schedule. Fourteen patients had a 50% or greater increase in absolute neutrophil count with amifostine treatment (range, 426 to 11,348/microL). Platelet count increased in 6 (43%) of 14 patients with thrombocytopenia (absolute increase, 16, 000 to 110,000/microL), and 5 of 15 red blood cell transfusion-dependent patients had a 50% of greater reduction in transfusion needs. Assayable hematopoietic progenitors increased in 13 of 15 evaluable patients; including CFU-GEMM (12), BFU-E (8), and CFU-GM (6). Amifostine doses less than or equal to 200 mg/m2 were well tolerated, whereas grade II nausea, vomiting, and fatigue was limiting at higher doses. Three patients with excess blasts before enrollment experienced an increase in BM blast percentage and two patients had evolution to acute leukemia that persisted after treatment withdrawal. We conclude that amifostine administered at doses </=200 mg/m2 three times a week is well tolerated and has hematologic activity in patients with MDS.
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PMID:Stimulation of hematopoiesis by amifostine in patients with myelodysplastic syndrome. 1153 40

Amifostine (WR-2721, Ethyol), S-2[3-aminopropylamino]-ethyl-phosphorothioic acid, was selected as a clinically usable radioprotector from more than 4,400 compounds in the 1950s. A considerable amount of preclinical work suggested that amifostine, or its activated thiol WR-1065, protected normal cells effectively against the adverse effects of irradiation and several anticancer drugs without exhibiting tumor protection. In non-randomized and randomized trials in malignant melanoma, colorectal cancer, head and neck cancer, non-small cell lung cancer, and epithelial ovarian carcinoma, amifostine significantly reduced the hematological and non-hematological toxicity of DNA-damaging agents such as alkylators, platinum compounds, or mitomycin C. In more recent studies, the drug also protected patients from side effects produced by taxanes or topoisomerase I inhibitors and is thus likely to allow higher cytostatic doses to be administered. Currently, there is no evidence that amifostine compromises the antineoplastic effect of the drugs studied. Otherwise, W/R-2721 may even improve the therapeutic efficacy of agents like cisplatin, carboplatin, or paclitaxel. Moreover, amifostine appears to produce growth-factor like properties resulting in growth-promoting effects on primitive blood progenitor cells ex vivo. Amifostine offers a rational approach to protect patients against chemotherapy-specific and often dose-limiting effects and is thus likely to improve therapeutic outcome significantly. Future studies should be focused on both new indications like childhood cancer, myelodysplastic syndromes, dose-intensified or high- dose chemotherapy, and multimodality approaches and optimization of amifostine dosage in order to reduce dose-limiting side effects. Then, the drug may play a major role in more specific and individualized oncologic strategies.
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PMID:Chemoprotection in anticancer therapy: the emerging role of amifostine (WR-2721). 970 84

Amifostine (Ethyol) is an analog of cysteamine that selectively protects normal tissues in multiple organ systems against the toxic effects of radiation and various cytotoxic drugs while preserving the antitumor effects of these therapies. Amifostine was evaluated in a multicenter, multinational phase III clinical trial that enrolled women with stage III/IV ovarian cancer. Its effects have also been studied using normal human bone marrow and human breast cancer cells, as well as leukemia cells. Additional clinical trials have shown that amifostine can protect normal tissues from the toxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes, and radiation. Other laboratory and clinical investigations indicate a potential role for this cytoprotective agent in the treatment of the ineffective hematopoiesis characteristic of the myelodysplastic syndromes.
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PMID:Clinical status and optimal use of amifostine. 1002 98

The phosphorylated thiol amine, amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA), is a cytoprotective agent for cisplatin-based chemotherapy. Recent investigations have given rise to new potential applications of amifostine in hematologic malignancies. Amifostine appears to exert a sustained mitogenic effect in primitive hematopoietic progenitors that results in a significant increase in colony-forming capacity. Amifostine also retards cell loss and delays commitment to apoptosis initiated by cytokine deprivation, suggesting that amifostine has trophic effects similar to the hematopoietic cytokines. The abilities to prolong progenitor survival and to delay apoptosis under conditions of cellular stress make amifostine an attractive agent for investigation in bone marrow failure states. Amifostine promotes more effective hematopoiesis in patients with myelodysplastic syndrome, although additional investigation is needed to further define the optimal dose and schedule of administration. Furthermore, amifostine may selectively enhance the cytotoxicity of chemotherapeutic agents in leukemia progenitors. When the sensitivity of leukemic and normal progenitors to mafosfamide was evaluated with and without amifostine pretreatment, amifostine effectively protected normal myeloid and erythroid progenitors while increasing leukemic cell kill. Thus, amifostine represents a unique agent with promising potential for therapeutic application in hematologic malignancies. Further investigation is needed to define its role in clinical practice.
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PMID:Use of amifostine in hematologic malignancies, myelodysplastic syndrome, and acute leukemia. 1034 62

Numerous dosing regimens have been used in the clinical development of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA). Whereas the current recommended dose of amifostine is 910 mg/m2 administered intravenously as a 15-minute infusion 30 minutes before chemotherapy, other studies have demonstrated cytoprotection with lower doses, suggesting that the optimal biologic dose may indeed be lower. Amifostine doses that protect against the toxicities associated with daily fractionated radiotherapy are also lower, with a dose range of 200 to 340 mg/m2 per fraction commonly reported in the literature. The toxicities most commonly associated with amifostine, namely, hypotension and nausea and vomiting, are dose related. They can be reduced using adequate prophylactic measures and can be effectively managed if they occur. Hypocalcemia and allergic reactions also can be lessened or averted with precautionary measures. Thus, although amifostine is generally well tolerated at the current recommended doses, clinical studies of variations in the approved dosing regimen would be useful in further defining the optimal amifostine dose for chemoprotection, for radioprotection, and for inducing hematopoiesis in patients with refractory myelodysplastic syndromes.
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PMID:Dosing considerations with amifostine: a review of the literature and clinical experience. 1034 69

Amifostine (Ethyol), the first broad-spectrum cytoprotectant approved in many countries for clinical use, is an analog of cysteamine and was originally developed by the U.S. Walter Reed Army Institute of Research in the 1950s as a radioprotective agent. Studies have shown that amifostine selectively protects normal tissues of various organs from the effects of radiation and multiple cytotoxic chemotherapeutic drugs. Amifostine has demonstrated broad-spectrum cytoprotection against myelotoxicity, nephrotoxicity, xerostomia, and mucositis associated with various chemotherapy and radiation modalities. Amifostine has been evaluated in large comparative clinical trials in patients with advanced ovarian cancer, rectal cancer, and head and neck cancer, and in many phase 2 trials in patients with various neoplastic diseases. These trials have shown that amifostine delivers protection from the cytotoxic effects of cisplatin, cyclophosphamide, and radiation on various organs. Pretreatment with amifostine has also improved salivary gland tolerance of high-dose radioiodine treatment. Recent unique observations include improvement in cytopenia in patients with myelodysplastic syndrome. This review summarizes preclinical and clinical data on amifostine and includes trials that evaluated the drug's chemoprotective and radioprotective effects and other potential uses in clinical oncology.
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PMID:Chemoprotective and radioprotective effects of amifostine: an update of clinical trials. 1119 8

The objective of this prospective study was to determine whether amifostine (Ethyol) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 x 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m(2) amifostine i.v. twice daily during conditioning (days -7 through -1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II-III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.
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PMID:Lack of cytoprotective effect of amifostine following HLA-identical sibling transplantation for advanced myelodysplastic syndrome (MDS): a pilot study. 1462 78