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

Ineffective haemopoiesis in the myelodysplastic syndromes (MDS) is mediated, at least in part, by apoptosis, though the mechanisms of apoptotic induction are unclear. Tumour necrosis factor-alpha (TNF-alpha) promotes apoptosis via intracellular oxygen free radical production, oxidation of DNA and proteins, and is increasingly implicated in the pathogenesis of MDS. Using single-cell gel electrophoresis, we have identified oxidized pyrimidine nucleotides in the progenitor-enriched bone marrow CD34+ compartment from MDS patients (P=0.039), which are absent in both CD34- MDS cells (P=0.53) and also CD34+ cells from normal subjects (P=0.55). MDS CD34+ blood cells also showed oxidized pyrimidine nucleotides compared with CD34- cells (P=0.029). Within normal subjects no differences were seen between CD34+ and CD34- bone marrow cell compartments. CD34+ bone marrow cell oxidized pyrimidines were strongly associated with elevated plasma TNF-alpha and low bone marrow mononuclear cell glutathione concentrations (5/6 patients) and the inverse relationship was also found (3/4 patients). This data implies a role for intracellular oxygen free radical production, perhaps mediated by TNF-alpha, in the pathogenesis of ineffective haemopoiesis in MDS and provides a rationale for the bone marrow stimulatory effects of antioxidants such as Amifostine in MDS.
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PMID:Oxidative DNA damage in CD34+ myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumour necrosis factor-alpha concentration. 940 Oct 76

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

Ineffective haemopoiesis leading to cytopenia presents the major clinical management problem for patients with myelodysplasia (MDS). Preliminary studies have demonstrated that the synthetic aminothiol Amifostine stimulates multilineage haemopoiesis both in vitro and in vivo in patients with MDS. We have treated 12 patients with an uninterrupted 8-week schedule of thrice-weekly intravenous Amifostine with a starting dose of 300 mg/m2 escalating to 450 mg/m2 in non-responders. No patients satisfied response criteria on study but two patients showed minor responses. We conclude that therapeutic response to Amifostine in MDS may be schedule dependent.
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PMID:Poor response rate to a continuous schedule of Amifostine therapy for 'low/intermediate risk' myelodysplastic patients. 985 31

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

An 11-year-old boy with multiply relapsed lymphoblastic disease became transfusion dependent with myelodysplasia and chromosomal abnormalities after 5 years of aggressive therapy. At 5 years of age, he presented with transient idiopathic hypoplastic anemia and neutropenia that spontaneously resolved within a month. Three months later, he experienced lymphoblastic lymphoma in the left parotid region and subsequently experienced disease relapse in his testicles, bone marrow, and central nervous system during a 3-year period. He has received multiagent chemotherapy, autologous peripheral blood stem-cell transplantation, and testicular and whole neuraxis irradiation therapy. After craniospinal irradiation, he did not recover normal bone marrow function. His bone marrow was hypocellular, and he required platelet and erythrocyte transfusions and granulocyte colony-stimulating factor. Marrow cytogenetic studies revealed new multiple translocations. Within a month of the initiation of intravenous amifostine at 200 mg/m2/dose three times a week, his leukocyte count, neutrophil count, and hemoglobin level normalized. His platelet count also improved sufficiently to achieve transfusion independence. He has returned to school and engages in other normal activities for his age. Amifostine may improve hematopoiesis in secondary myelodysplastic syndromes in children.
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PMID:Improved hematopoiesis using amifostine in secondary myelodysplasia. 1059 67

Thirty-five patients with myelodysplastic syndrome (MDS) were registered on protocol MDS 96-02 and were receiving continuous therapy with pentoxifylline 800 mg 3 times a day and ciprofloxacin 500 mg twice a day by mouth; dexamethasone was added to the regimen for the partial responders and the nonresponders after 12 weeks at a dose of 4 mg by mouth every morning for 4 weeks. Amifostine was administered intravenously 3 times a week at 3 dose levels (200 mg/M(2), 300 mg/M(2), and 400 mg/M(2)) to cohorts of 10 patients each. Therapy has been continued for 1 year in responders. Twenty-nine have completed at least 12 weeks of therapy and are available for response evaluation. Of the 21 men and 8 women (median age, 67 years), 20 had refractory anemia (RA), 3 had RA with ringed sideroblasts (RARS), 5 had RA with excess blasts (RAEB), and 1 had chronic myelomonocytic leukemia (CMMoL). Five had secondary MDS. No differences were noted in response rates among the 3 dose levels. Seven patients did not respond at all, and 22 showed an improvement in cytopenias (76%). Three had a triple lineage response, 10 had a double lineage response, and 9 had a single lineage response (8 of 9 in absolute neutrophil count [ANC] and 1 had more than a 50% reduction in packed red blood cell transfusions). Fifteen patients responded only after the addition of dexamethasone, whereas 7 responded before. When examined by lineage, 19 of 22 showed improved ANC, 11 of 22 demonstrated more than 50% reduction in blood transfusions, improved Hb levels, or both, and 7 of 22 showed improvement in platelet counts. Interestingly, the responses were frequently slow to appear, and continued improvement in counts was seen up to 12 months of therapy and beyond. This study supports the feasibility of treating patients with MDS with the unique approach of cytoprotection and anticytokine therapies as well as the principle that prolonged commitment to treatment is desirable when noncytotoxic agents are administered. (Blood. 2000;95:1580-1587)
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PMID:Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone. 1068 11

Amifostine is the agent of proved cytoprotective activity against alkylating drugs and rubidomycine. Its protective effect against other cytotoxic drugs is doubtful. BFM-83 induction therapy for ANLL (ARA-C + RUB + VP-16) which is applied to children with acute non-lymphoblastic leukemia (ANLL) commonly contributes to severe adverse reactions. We administered amifostine to three children: 2 boys with ANLL (7 and 11 yrs) and 1 girl with MDS (3 yrs) during etoposide and rubidomycine induction therapy in order to decrease chemotherapy-related adverse reactions. Doses of amifostine were 740 mg/m2, 910 mg/m2 and 910 mg/m2 respectively. Efficacy of the therapy was evaluated on the base of blast decline in the bone marrow, efficacy of the cytoprotection by myelo and nephrotoxicity symptoms analysis. Chemotherapy-related adverse effects in the children protected by amifostine were less severe and observed by the shorter periods as compared with the historical control group of 20 patients treated according to BFM-83 without cytoprotection. These cases show the potential beneficial effect of amifostine during BFM-83 induction therapy for ANLL. The further randomised clinical study of the proposed cytoprotection should be performed to establish its value.
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PMID:[Cytoprotective effect of amifostine in children during induction therapy according to BFM-83: report on cases]. 1073 72


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