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 myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic disorders derived from an abnormality affecting a multipotent hematopoietic stem cell. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of the pyrimidine nucleoside cytosine, as a continuous intravenous infusion, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 evaluable patients: five (12%) in complete remission (CR, complete normalization of bone marrow and peripheral blood counts); 11 (25%) in partial remission (PR, > or = 50% restoration of the deficit from normal of all three peripheral blood cell lines, elimination of transfusion requirements, and a decrease in percentage bone marrow blasts by > or = 50% from prestudy values); five (12%) improved (> or = 50% restoration in the deficit from normal of one or more peripheral blood cell lines and/or a > or = 50% decrease in transfusion requirements). A trilineage improvement (CR and PR) occurred in 37% of the patients. The median survival for all patients was 13.3 months and the median duration of remission for those with CR and PR was 14.7 months. Mild to moderate nausea and/or vomiting was the most common side effect (63%). Myelosuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33% of the patients. Prior to treatment, bone marrow erythroid progenitor cells were assayed in vitro. Colonies derived from erythroid burst-forming units (BFU-e) were undetectable in one patient and reduced in two. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two patients with detectable colony growth prior to treatment, colony number decreased by day 8 of the first cycle, followed by a subsequent increase. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony number correlated with the spontaneous rise in hemoglobin levels and red cell transfusion independence.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. 768 52

A conventional and a computer search of the literature yielded 627 sequenced point mutations in the ras and p53 genes in 575 patients with leukaemia and myelodysplasia (MDS) out of a total of 4214 investigated. ras Mutations predominated in myeloid leukaemia and were more common in the disease in relapse than at presentation. There was no clinical, or haematological difference or difference in survival between ras positive and ras negative patients with acute myeloid leukaemia (AML) in adults or children, but ras mutations carried a poorer prognosis in childhood acute lymphocytic leukaemia and an increased risk of leukaemia in MDS. p53 mutations predominated in lymphoid leukaemia and were several fold more frequent in leukaemia in relapse than in the de novo disease, were associated with loss of the normal p53 allele (monosomy 17) in > 50% of cases and carried a poor prognosis in AML, MDS and chronic lymphatic leukaemia and a 3.8-fold increase risk of death in T cell acute lymphocytic leukaemia. There were 163 transitions for every 100 transversions, the expected number being ca 50. Consideration of the molecular mechanisms by which nitrous acid produces transitions allows transitions resulting from the deamination of cytosine to be distinguished from those resulting from the deamination of adenine. The former constitute 84.67% and the latter 15.33% of the 372 transitions present. Again purine-->pyrimidine and pyrimidine-->purine transversions form 80.35 and 19.65%, respectively, of the 228 transversions present. The possible bearing of this highly non-random distribution on the aetiology of point mutations in leukaemia and myelodysplasia is discussed.
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PMID:The non-random distribution of point mutations in leukaemia and myelodysplasia--a possible pointer to their aetiology. 927 67

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

Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and antileukemia activity. Azacitidine has been shown to have survival benefits in patients with high-risk myelodysplastic syndrome (MDS), and has activity in the treatment of acute myelogenous leukemia (AML). It is administered by subcutaneous (s.c.) or intravenous (i.v.) injection daily at a dose of 75 mg/m(2) for 7 days every 4 weeks. An oral formulation would facilitate dosing, reduce administration side effects and potentially maximize azacitidine pharmacologic action. Previously, oral formulations of this class of agent have failed due to rapid catabolism by cytidine deaminase and hydrolysis in aqueous environments. Development of a film-coated formulation has circumvented this difficulty. In a formulation feasibility pilot study, four subjects with solid malignant tumors, AML or MDS received single oral doses of 60 or 80 mg azacitidine. Subjects demonstrated measurable plasma concentrations of azacitidine, allowing bioavailability comparisons to be made to historical pharmacokinetic data for s.c. azacitidine. Subjects safely tolerated 80 mg, a dose for which the mean bioavailability was 17.4% of historic s.c. exposure. No severe drug-related toxicities were observed. These data suggest that oral azacitidine is bioavailable in humans and should be studied in formal phase 1 trials.
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PMID:A pilot pharmacokinetic study of oral azacitidine. 1854 3

Bone marrow aspirates of 19 patients with low-risk myelodysplastic syndromes (MDS) and 14 control subjects were collected in order to assess the level of oxidative DNA damage. Glycophorin A positive and negative cells separated by miniMACS magnetic cell sorting were subjected to single cell gel electrophoresis (comet assay) combined with enzymes of base excision repair (endonuclease III and formamido-pyrimidine-glycosylase) that specifically recognize oxidized nucleotides. Compared to controls, MDS patients exhibited a significant increase of oxidative damage to DNA which could contribute to genomic instability and disease progression.
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PMID:Oxidative DNA damage in bone marrow cells of patients with low-risk myelodysplastic syndrome. 1868 69

The myelodysplastic syndromes (MDS) encompass a heterogeneous group of malignant hematologic disorders characterized by ineffective hematopoiesis, peripheral cytopenias, frequent karyotypic abnormalities and significant risk for transformation to acute myeloid leukemia (AML). The prognosis of patients with intermediate- or high-risk MDS is very poor. This is due to the fact that standard therapeutic options are largely palliative. Neither autologous stem cell transplantation (SCT) nor chemotherapeutic regimens have been shown to prolong survival in patients with MDS. Allogeneic SCT, while potentially curative, is only available to a selected group of patients and is associated with high morbidity and mortality in elderly patients, which constitute the majority of patients with MDS. Hypermethylation of tumor-suppressor genes has been invoked as an important pathogenetic mechanism in MDS. The pyrimidine nucleoside analog azacitidine, which inhibits DNA methyltransferases, has recently become the first therapeutic to prolong survival in patients with MDS, thus changing the natural history of these malignancies. The activity of azacitidine in MDS has spurred the development of combinations of this agent with other epigenetic modifiers for the treatment of MDS and AML.
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PMID:Azacitidine for the treatment of myelodysplastic syndrome. 1958 26

Azacitidine (Vidaza) is a pyrimidine nucleoside analogue of cytidine. Subcutaneous azacitidine was recently approved in the EU for the treatment of adults who are not eligible for haematopoietic stem cell transplantation and who have intermediate-2-risk or high-risk myelodysplastic syndromes (MDS) [according to International Prognostic Scoring System (IPSS) criteria], chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder, or acute myeloid leukaemia (AML) with 20-30% blasts and multilineage dysplasia (according to the WHO classification). Subcutaneous azacitidine is the only drug shown to significantly prolong survival in patients with higher-risk MDS or WHO-defined AML, compared with conventional care (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). In addition, azacitidine is associated with a lower risk of AML progression and higher rates of complete remission, partial remission, haematological improvement and red blood cell (RBC) transfusion independence. Azacitidine has an acceptable tolerability profile; peripheral cytopenias are the most commonly occurring adverse event. Thus, azacitidine is a valuable option for the first-line treatment of patients with higher-risk MDS/AML.
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PMID:Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. 1991 60

The pyrimidine analogs, 5-azacytidine (azacitidine, Vidaza) and its deoxy derivative, 5-aza-2'-deoxycytidine (decitabine, Dacogen, are the most widely used inhibitors of DNA methylation which trigger demethylation leading to a consecutive reactivation of epigenetically silenced tumor suppressor genes in vitro and in vivo. Although the antileukemic capacity of decitabine has been known for almost 40 years, its therapeutic potential in hematologic malignancies is still under intensive investigation. Multiple clinical trials have shown the promising activity of low-dose decitabine in AML, MDS, CML, and hemoglobinopathies, whereas its efficacy in solid tumors is rather limited.Clinical responses appear to be induced by both epigenetic alterations and the induction of cell-cycle arrest and/or apoptosis. Recent clinical trials have been investigating new dosing schedules, routes of administration, and combination of decitabine with other agents, including histone deacetylase (HDAC) inhibitors.
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PMID:Decitabine. 2007 36

Disease remission in patients with myelodysplastic syndromes can be achieved with azanucleosides, which act as pyrimidine analogs and hypomethylating agents. However, despite treatment with azanucleoside induction, patients with myelodysplastic syndromes nearly always relapse. Allogeneic hematopoietic cell transplantation (HCT) can be curative, but it is risky. Given that azanucleosides affect human leukocyte antigen expression and lymphocyte reactivity, we conducted a retrospective study to define the impact of pre-HCT azanucleoside therapy on post-HCT donor chimerism. Patients receiving azanucleoside induction therapy achieved rapid and high levels of donor chimerism post-transplant. Lineage analysis also found rapid donor chimerism of lymphocyte and granulocyte subsets. These data indicate the feasibility of pretransplant azanucleoside therapy in patients who subsequently receive an HCT.
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PMID:Hypomethylating agent induction therapy followed by hematopoietic cell transplantation is feasible in patients with myelodysplastic syndromes. 2035 82

Azacitidine is a pyrimidine nucleoside analog licensed for treatment of adult patients with myelodysplastic syndrome. Azacitidine acts as an inducer of cell differentiation by causing demethylation and re-expression of genes silenced by hypermethylation. We report a 56-year-old man with myelodysplastic syndrome who developed interstitial lung disease after azacitidine therapy. Open lung biopsy revealed a nonresolving organizing pneumonia pattern and bronchocentric granulomatous pattern suggestive of drug-induced lung injury. Treatment with steroids and discontinuation of azacitidine led to resolution of interstitial lung disease. The Naranjo adverse drug reaction probability scale score indicated that the association between azacitidine and interstitial lung disease was probable. Interstitial lung disease is a serious but uncommon side effect of this relatively safe drug. The mechanism underlying this is still unclear. The patient was subsequently treated with decitabine with no recurrence of interstitial lung disease.
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PMID:Interstitial lung disease associated with azacitidine use: a case report. 2063 71


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