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 syndromes (MDS) are a heterogeneous group of disorders with an invariably fatal outcome. Other than bone marrow transplantation, no treatment has been able to alter the natural history of MDS. As a result, there has been an interest in identifying new and more effective chemotherapeutic agents. Many of the drugs that have been evaluated in an attempt to increase remissions and prolong survival were selected because of their activity in acute myeloid leukemia. Thus cytarabine has been the most widely studied drug. Although numerous studies suggested activity for low-dose cytarabine (LoDAC), a careful analysis of the data identified a complete remission (CR) rate of less than 20%, without meaningful clinical benefit. The issue of LoDAC was finally put to rest by a randomized trial in which survival was no better than with supportive care. 5-Azacytidine induces cellular differentiation by hypomethylation of DNA. Phase II trials noted CRs in fewer than 10% of patients, with response rates under 30%, although additional patients appeared to experience hematologic and clinical benefit. A randomized trial of 5-azacytidine versus supportive care failed to demonstrate a survival benefit. One of the most promising new agents is the topoisomerase inhibitor topotecan, which achieves CRs in more than 30% of patients. Combinations of this drug with other active agents are in development. Obviously, new treatment strategies are needed to improve the outcome of MDS patients. Combination approaches incorporating new, active agents should have sound scientific rationale, targeting biological differences among the various MDS subtypes.
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PMID:Standard and low-dose chemotherapy for the treatment of myelodysplastic syndromes. 973 95

Azacitidine is a new drug with a novel mechanism of action; it can correct abberant gene expression in patients with myelodysplastic syndrome. The drug improves symptoms, decreases the need for transfusions, reduced the rate of transformation to leukemia and probably improves survival.
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PMID:Azacitine (vidaza) for myelodysplastic syndrome. 1567 15

On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular approval by the U.S. Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome (MDS). This report summarizes the basis for this approval. Effectiveness was demonstrated in one randomized, controlled trial comparing azacitidine administered s.c. with best supportive care (observation group) and in two single-arm studies, one in which azacitidine was administered s.c. and in the other in which it was administered i.v. The dose of azacitidine, 75 mg/m2/day for 7 days every 28 days, was the same in all three studies. In the randomized trial, study participants were well matched with respect to age, sex, race, performance status, MDS subtype, and use of transfusion during the 3 months before study entry. Patients in the observation arm were permitted by protocol to cross over to azacitidine treatment if their disease progressed according to prespecified criteria. During the course of the study, more than half of the patients in the observation arm did cross over to the azacitidine treatment arm. The primary efficacy end point was the overall response rate. Response consisted of complete or partial normalization of blood cell counts and of bone marrow morphology. The response rate in the azacitidine arm was about 16%; there were no responses in the observation arm. The response rates in the two single-arm studies were similar (13% and 19%). The responses were sustained, with median durations of 11 months and 17 months respectively. Responding patients who were transfusion dependent at study entry lost the need for transfusions. In addition, about 19% of patients had less than partial responses (termed improvement), and two-thirds of them became transfusion independent. Common adverse events associated with azacitidine treatment were gastrointestinal (nausea, vomiting, diarrhea, constipation, and anorexia), hematologic (neutropenia, thrombocytopenia), fevers, rigors, ecchymoses, petechiae, injection site events, arthralgia, headache, and dizziness. Liver function abnormalities occurred in 16% of patients with intercurrent hepatobiliary disorders and in two patients with previously diagnosed liver cirrhosis. Renal failure occurred in patients during sepsis and hypotension. There were no deaths attributed to azacitidine. Azacitidine, the first drug approved by the U.S. FDA for MDS, has a favorable safety profile and provides a clinical benefit of eliminating transfusion dependence and complete or partial normalization of blood counts and bone marrow blast percentages in responding patients.
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PMID:FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. 1579 20

Azacitidine (Vidaza; Pharmion), an inhibitor of DNA methylation, was approved by the US FDA for the treatment of myelodysplastic syndromes in May 2004. It is the first drug to be approved by the FDA for treating this rare family of bone-marrow disorders, and has been given orphan-drug status. It is also a pioneering example of an agent that targets 'epigenetic' gene silencing, a mechanism that is exploited by cancer cells to inhibit the expression of genes that counteract the malignant phenotype.
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PMID:Azacitidine. 1596 22

Higher risk myelodysplastic syndromes (MDS) include patients in the Intermediate-2 and high-risk categories of the International Prognostic Scoring System, as well as patients with MDS secondary to radiation or chemical exposure. Ideally, the goal of therapy is to alter the natural history of disease in these patients to achieve cure or durable remission. High-intensity chemotherapy can achieve moderate rates of complete remission, however, durability of remission and overall survival tend to be short. Hematopoietic stem cell transplantation (HSCT) offers the possibility of cure, with long-term disease-free survival inversely related to age. Patients who are elderly or have poor functional status are candidates for reduced intensity HSCT, although this is still an experimental modality. Azacitidine is a hypomethylating agent that is a reasonable option for many patients ineligible for high-intensity therapies. Other therapies, such as immunomodulatory agents, arsenic trioxide, and farnesyl transferase inhibitors have thus far shown limited usefulness in higher risk MDS. This paper reviews the various therapeutic options for higher risk MDS, providing rationale for specific management approaches for these patients.
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PMID:Management of patients with higher risk myelodysplastic syndromes. 1597 21

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, leading to bone marrow failure and peripheral blood cytopenias. MDS is difficult to diagnose because of the absence of symptoms in the early stage of the disease; it often is discovered accidentally during routine physical examinations or blood tests. The U.S. Food and Drug Administration approved azacitidine (Vidaza, Pharmion Corporation, Boulder, CO) for the treatment of MDS. Prior to the approval of azacitidine, no approved therapies were available for the treatment of MDS. Azacitidine is believed to exert its anticancer effects by induction of hypomethylation and cytotoxicity. In clinical studies, the most common adverse events during treatment with azacitidine included nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection-site erythema, constipation, neutropenia, and ecchymosis. To ensure proper treatment with azacitidine, nurses should have an understanding of dosage and administration guidelines, commonly observed adverse events, monitoring and care of adverse events, and monitoring of laboratory tests. Having a comprehensive understanding of MDS, its underlying disease characteristics, and current treatments will enable oncology nurses to provide optimal patient care.
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PMID:Advances in myelodysplastic syndrome: nursing implications of azacitidine. 1611 8

The class of DNA methyltransferase inhibitors is represented by azacitidine and decitabine. Azacitidine is approved for the treatment of patients in both low- and high-risk subtypes of myelodysplastic syndrome (MDS), and decitabine is currently under review by the FDA. Azacitidine phase III trial data, based upon the Cancer and Leukemia Group B (CALGB) study 9221, showed durable clinical and symptomatic improvement in bone marrow function, a reduction in the risk of leukemic transformation, and significant improvements in the quality of life of patients treated with azacitidine compared with supportive care alone. This study also provided data suggestive of improvement in survival in MDS patients. The experience with decitabine comprises a number of phase I/II studies and a phase III trial yet to be published. While there is a strong base of experience supporting the efficacy of DNA methyltransferase inhibitors in the treatment of MDS, a number of practical issues need to be explored further. These include the optimization of the timing and duration of treatment, and the prediction of response to therapy. Along with current experience, future studies will lead to the development of treatment algorithms, strategies for selecting patients (e.g. according to age, risk, classification, and cytogenetic profile), and the combination strategies, particularly with histone deacetylase inhibitors, in the management of MDS.
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PMID:Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. 1634 Dec 36

Azacitidine (Vidaza, Pharmion Corp., Boulder, CO, USA) and decitabine (Dacogentrade mark, SuperGen, Inc., Dublin, CA, USA, and MGI Pharma, Inc., Bloomington, MN, USA) are DNA methyltransferase (DNMT) inhibitors that have clinical activity in patients with myelodysplastic syndromes. Mechanism-based laboratory studies suggest that clinical optimization of therapy with DNMT inhibitors needs to include optimizing intracellular drug uptake and maximizing drug exposure over time while still using lower doses to avoid cytotoxicity. Clinical studies suggest that increased dose intensity and multiple cycles of administration substantially increase response rates. Other strategies for optimizing the efficacy of DNMT inhibitor therapy also include identification of patients that are best qualified for treatment, and defining in vivo mechanisms of patient responses. In the future, combination strategies to increase gene reactivation and to take advantage of increased expression of target genes may be critical for achieving optimal results.
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PMID:Optimizing therapy with methylation inhibitors in myelodysplastic syndromes: dose, duration, and patient selection. 1634 Dec 37

For patients with acute myeloid leukemia refractory to intensive chemotherapy prognosis is very poor and treatment options are limited. 5-Azacytidine, a demethylating drug, is effective in the treatment of myelodysplastic syndromes when administered at a low-dose, subcutaneously. We report a case of a patient with AML refractory to induction chemotherapy as well as to two high-dose salvage regimens. The patient achieved CR through monotherapy with low-dose azacytidine.
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PMID:Induction of complete remission in a patient with acute myeloid leukemia refractory to high-dose chemotherapy through treatment with 5-azacytidine. 1689 Feb 86

Epigenetic silencing of regulatory genes by aberrant methylation contributes to tumorigenesis. DNA methyltransferase inhibitors (DNMTI) represent promising new drugs for anti-cancer therapies. The DNMTI 5-Azacytidine is effective against myelodysplastic syndrome, but induces switching of latent to lytic Epstein-Barr virus (EBV) in vitro and results in EBV DNA demethylation with the potential of induction of lytic EBV in vivo. This is of considerable concern given that recurrent lytic EBV has been linked with an increased incidence of EBV-associated lymphomas. Based on the distinct properties of action we hypothesized that the newer DNMTI Zebularine might differ from 5-Azacytidine in its potential to induce switching from latent to lytic EBV. Here we show that both 5-Azacytidine and Zebularine are able to induce expression of E-cadherin, a cellular gene frequently silenced by hypermethylation in cancers, and thus demonstrate that both DNMTI are active in our experimental setting consisting of EBV-harboring Burkitt's lymphoma Akata cells. Quantification of mRNA expression of EBV genes revealed that 5-Azacytidine induces switching from latent to lytic EBV and, in addition, that the immediate-early lytic infection progresses to early and late lytic infection. Furthermore, 5-Azacytidine induced upregulation of the latent EBV genes LMP2A, LMP2B, and EBNA2 in a similar fashion as observed following switching of latent to lytic EBV upon cross-linking of the B-cell receptor. In striking contrast, Zebularine did not exhibit any effect neither on lytic nor on latent EBV gene expression. Thus, Zebularine might be safer than 5-Azacytidine for the treatment of cancers in EBV carriers and could also be applied against EBV-harboring tumors, since it does not induce switching from latent to lytic EBV which may result in secondary EBV-associated malignancies.
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PMID:Zebularine reactivates silenced E-cadherin but unlike 5-Azacytidine does not induce switching from latent to lytic Epstein-Barr virus infection in Burkitt's lymphoma Akata cells. 1721 5


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