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)

Amifostine (AMF), a phosphorylated aminothiol, has been used to treat myelodysplastic syndrome (MDS), where it produces a stimulatory effect on hematopoiesis in bone marrow. To determine if AMF also produced a direct effect on human MDS cells, we planned a study to evaluate the effect of a continuous exposure to AMF on a human MDS cell line. AMF was shown to have a growth-inhibitory effect on MDS cells, with an IC(50) of 14 microM after a 5 day exposure. Cell cycle analysis revealed that a 5 day exposure to 20 microM AMF increased the percentage of cells in G0/G1 and this was accompanied by a decrease in the percentage of cells in S phase. Cytoflorometric and agarose-gel electrophoretic analysis revealed that this effect correlated with cell membrane alterations and DNA fragmentation consistent with an induction of apoptosis without affecting the expression of p53 protein or inducing any lymphoid or myeloid differentiation in the MDS cell line. We conclude that the continuous exposure of a human MDS cell line to AMF is cytotoxic and associated with an induction of apoptosis independent of alterations in p53 expression.
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PMID:Amifostine cytotoxicity and induction of apoptosis in a human myelodysplastic cell line. 1078 87

Amifostine increases in vitro burst-forming unit-erythroid and colony-forming unit-granulocyte/granulcoyte-macrophage cultured from bone-marrow cells from patients with myelodysplastic syndrome (MDS). Several small clinical studies give divergent informations about the potential of amifostine as single agent to improve hematopoiesis in MDS patients. In these studies, patients with refractory anemia (RA), RA with excess of blasts (RAEB), and RAEB in transformation (RAEB-T) were analyzed together, resulting in response rates varying from 8% to 30%. The present multi-center study evaluated whether treatment with amifostine is of clinical benefit in patients with RA who are transfusion dependent. The effect on transfusion frequency as well as on platelets and absolute neutrophil count (ANC) was examined in 14 patients with RA [median age 67 years (55-72 years), male:female 9:5]. Four treatment cycles were planned, each consisting of intravenous amifostine at 200 mg/m2/day three times per week followed by a 2-week interval. Since tumor necrosis factor (TNF) alpha is a main suppressive cytokine for hematopoiesis in RA patients, serum samples for analyzing endogenous levels of TNF alpha were collected prior to the study and after four treatment cycles. In three patients (21%), reduced transfusion requirement with prolongation of the transfusion interval from 4 weeks to 8 weeks (two patients) and 4 weeks to 6 weeks was seen. An increase in ANC from 400/microliter to 2600/microliter and 200/microliter to 3400/microliter was observed in two patients. Platelets increased from 129,000/microliter to 277,000/microliter in an additional patient. In one patient, disease progression from RA to RAEB was observed. Serum TNF alpha levels were increased in MDS patients compared with normal controls (18.8 pg/ml vs 9.1 pg/ml), and there was no change during the treatment with amifostine (17.5 pg/ml). In conclusion, treatment with amifostine as a single agent was of limited benefit in patients with RA. The serum TNF alpha levels were unchanged during treatment with amifostine in RA patients.
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PMID:Effect of treatment with amifostine used as a single agent in patients with refractory anemia on clinical outcome and serum tumor necrosis factor alpha levels. 1087 Apr 80

Twenty patients with poor prognosis AML and four patients in the blastic phase of a myeloproliferative disorder were treated with two 'pulses' of therapy each consisting of two doses of high dose araC (separated by 12 h) followed by a single dose of mitoxantrone. The pulses were separated by 96 h. Amifostine was then administered tiw. The median age of the population was 68 years with 88% of patients having had either a prior MDS, MPD or toxic exposure. The acute leukemia of 58% of patients either entered a CR or reverted to preleukemic state. For patients under 70 years of age, treatment produced 62% CRs with a leukemia free decision marrow in 77%. For patients over 70 years the CR rate was 27% with 36% of patients having a leukemia free decision marrow.
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PMID:Poor prognosis acute myelogenous leukemia: 1 - response to treatment with high dose cytarabine/mitoxantrone/ethyol @ (Amifostine). 1093 21

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

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).
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PMID:Amifostine: chemotherapeutic and radiotherapeutic protective effects. 1133

Amifostine is a cytoprotective agent mainly used in cancer therapies, in order to ameliorate the toxic effects of anticancer chemotherapy and radiotherapy. In the past years an intriguing number of applications of amifostine have been identified; one of these is bone marrow cells protection and stimulation. Amifostine was administered in seven patients with myelodysplastic syndromes, four males and 3 females aged between 67 and 78 years old, in order to estimate its efficacy in reducing the need for red blood cells transfusions. Two patients had RAEB, four RA and one RARS. The drug was administered in an outpatient basis in a dose of 300 mgr/m2, three times weekly for at least four weeks. We administered at the same time erythropoietin 10.000 U subcutaneously. All patients received daily supplementation of oral ferrum sulfate and folic acid. Three patients, a woman with RA and two men, one with RA and another with RAEB improved the levels of Hb beyond 12,0 gr/dl and did not receive blood transfusions after the second week of treatment. The drug was well tollerated without any side effects in all of the patients.
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PMID:Preliminary results of amifostine administration in combination with recombinant human erythropoietin in patients with myelodysplastic syndromes. 1137 Aug 27

Twenty five patients with AML who had neither a history of toxic exposure or myelodysplasia were treated with a remission induction regimen consisting of two pulses of chemotherapy separated by 96 hrs. Each pulse consisted of cytarabine 2gm/m(2) (at t=0 and t=12 hrs) with mitoxantrone [30mg/m(2) ] administered immediately after the second cytarabine administration. Amifostine was administered three times a week [on Monday, Wednesday, and Friday] until the outcome of therapy was known. This regimen induced complete remissions in 15 of 17 patients less than 70 years of age and in 5 of 8 patients older than 70 years.
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PMID:High remission rate in acute myeloblastic leukemia with only two days of chemotherapy. 1137 45

Amifostine (AMF) promotes in vitro growth and survival of hematopoietic progenitors. In this study we evaluated the efficacy of AMF in the treatment of anemia in patients with low-risk myelodysplastic syndromes (MDS) and the possible predicting value for response to AMF therapy of two types of in vitro clonogenic assays. Two different doses of AMF, 300 mg/m2 (group A, 11 patients) or 400 mg/m2 (group B, 16 patients), were studied. AMF was given three times weekly for 3 weeks, i.v., followed by 2 weeks off therapy. Patients were evaluated after two cycles of treatment. Partially or nonresponding patients of group A received 400 mg/m2 AMF and were reevaluated. An increase of hemoglobin (Hb) values of more than 2 g/dl and a 100% decrease in transfusion requirements for at least 6 weeks were defined as a complete response (CR) while an increase of Hb values of 1-2 g/dl or a 50% decrease in transfusion requirements was considered as a partial response (PR). In group A, two out of 11 (18.1%) patients achieved a CR with the initial dose and one of the nine that received 400 mg/m2 AMF achieved a PR. In group B, three out of 16 (18.7%) patients achieved a PR; the overall response rate in both groups was 22.2%. In group A, bone marrow progenitor assay was performed pre- and post-amifostine treatment. Erythroid burst-forming units (BFU-E) were increased in six out of 11 (54.5%) patients, and this increase preceded the rise in Hb levels in three of them. In group B, a clonogenic assay was performed in 11 out of 16 patients before AMF treatment. In vitro results after pretreatment with 500 microM amifostine confirmed the response of two MDS patients that achieved a PR. No response in vitro was observed in all eight nonresponding patients and in one PR patient. The lack of response in the clonogenic assays predicted for nonresponse to treatment with a predictive power of 91.8%. We conclude that 300 mg/m2 is an adequate initial treatment for low-risk MDS patients and both clonogenic assays have a strong predicting value for response to treatment.
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PMID:Treatment of anemia in low-risk myelodysplastic syndromes with amifostine. In vitro testing of response. 1197 18

Amifostine, a phosphorylated thiol-amine, is known as a cytoprotective agent especially for cisplatin containing chemotherapies. Apart from the cytoprotective role, Amifostine could also be used in the treatment of hematologic malignancies such as myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML), as a treatment option or for potentiating the effects of cytotoxic agents. We tried to use Amifostine in a patient with AML, which did not respond to conventional cytotoxic chemotherapy and aimed to publish the results. The patient was a 77-year-old male patient, he was diagnosed as AML by peripheral blood smear and bone marrow aspiration. Treatment commenced with low dose cytosine arabinoside (Ara-C) but the therapy should have ceased due to patient intolerance. The patient refused further therapy and he was offered to have Amifostine treatment. Amifostine was administered 200 mg/m2 three times a week, with ciprofloxacin, pentoxifyllin and dexamethasone. Dramatic response was obtained after 8 weeks of administration. Blast rate was reduced from 35 to 7% in bone marrow aspiration; pancytopenia was restored to normal levels. This remission was maintained through 8 more weeks. Amifostine treatment was restarted after he relapsed but this time he did not respond to the treatment and died of gastrointestinal bleeding on the 8th week of treatment.
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PMID:Acute myeloblastic leukemia achieving complete remission with amifostine alone. 1199 88

Amifostine is a phosphorylated aminothiol that has besides anti-oxidative and cytoprotective properties, also survival- and growth-promoting effects on hematopoietic progenitor cells. Clinical studies have demonstrated that infusions with amifostine are able to increase erythro-, myelo-, and thrombopoiesis in some patients with myelodysplastic syndromes (MDS). Since clonal and non-clonal progenitors can coexist in early phase MDS, we have studied if amifostine exerts a selective growth-promoting effect on clonal or non-clonal cells. For this purpose, purified CD34(+) marrow progenitors from nine female MDS patients were grown in short- and long-term cultures. Clonality was studied on individual colonies using polymorphisms in the human androgen receptor assay (HUMARA) locus. Three patients had growth of residual non-clonal progenitors at baseline. Continuous exposure to 100nM amifostine exerted a growth-promoting effect on progenitors in 50% of the patients. HUMARA patterns of individual colony-forming unit granulocyte macrophage (CFU-GM; 5/9) and 5 week long-term culture-initiating cells (LTC-IC; 2/9) were compared without and with amifostine exposure. We did not observe preferential stimulation of clonal or non-clonal progenitors. Based on these results, the stimulation of committed and immature progenitor growth in MDS by amifostine, is non-selective and does not favor nor suppress the growth of residual non-clonal cells.
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PMID:Amifostine does not preferentially stimulate the growth of residual polyclonal progenitor cells in myelodysplastic syndromes. 1268 58


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