UMLS:C0023467 - FACTA Search

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Query: UMLS:C0023467 (acute myeloid leukemia)
35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Aza-2'-deoxycytidine (Decitabine) is a new cytosine analog with potent antileukemic activity and able to induce in vitro gene activation and cellular differentiation by a mechanism probably involving DNA hypomethylation. The aim of this pilot study was to evaluate the efficacy and the toxicity of Decitabine, used as single induction agent, in the treatment of poor prognosis acute myeloid leukemia (AML) patients, and to explore its mechanism of action. A total of 12 patients were treated with Decitabine at 90-120 mg/m2 as a four hour intravenous infusion, three times daily for three consecutive days every four to six weeks. A minimum of two courses were required for response evaluation and to consider a patient as therapeutic failure. A total of 10/12 patients were fully evaluable for response; three patients achieved a complete remission (CR) and one a partial remission (PR). Extra-hematological toxicity was generally mild. As for the mechanism of action, both a differentiation induction effect and a cytotoxic mechanism have been observed. In particular, CRs and PRs were probably obtained through the induction of leukemia cell differentiation as shown by the kinetic of remission and immunotyping studies. The preliminary results of this ongoing study suggest that Decitabine may have a prominent role in the treatment of those AML patients with poor general conditions and/or advanced age.
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PMID:Pilot study of 5-aza-2'-deoxycytidine (Decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results. 768 55

5-Aza-2'-deoxycytidine (Decitabine) is an analog of deoxycytidine now entering clinical trials in acute myeloid leukemia (AML) owing to a defined antileukemic activity mediated at least in part by DNA hypomethylation, altered gene expression, and induction of cell differentiation. In the present study, we examined the relationship between the in vitro sensitivity to Decitabine of blast progenitors and the clinical outcome, in nine AML patients treated in vivo with Decitabine within a phase II trial carried out at two different institutions. Leukemic blast progenitors in acute myeloid leukemia (AML) undergo terminal divisions giving rise to colonies in methylcellulose. The self-renewal capacity of blast progenitors is conversely reflected by a secondary methylcellulose assay after exponential growth of clonogenic cells in suspension cultures. Three out of four patients, in which clonogenic cells in methylcellulose were strongly suppressed by Decitabine and clonogenic growth of blasts cultured in suspension was only slightly affected, failed on Decitabine treatment in vivo. Two subjects, whose blast progenitors in suspension culture were significantly inhibited by Decitabine, obtained a positive hematological response (complete or partial remission, CR or PR) and an additional patient showing a similar in vitro pattern died in induction with an hypoplastic marrow without morphological evidence of persistant leukemia. Interestingly two patients displaying an unfavourable in vitro pattern (i.e. a minor suppression of self-renewal mitoses as evinced from suspension cultures) achieved a hematological response (CR and PR) upon in vivo therapy with Decitabine. The in vitro response to Decitabine of clonogenic progenitors from both these patients shifted to a favourable pattern (i.e. major suppression of self-renewal versus terminal mitoses) following manipulation of culture conditions by the addition or removal of exogenous growth factors. In addition, in a further patient refractory to treatment with Decitabine in vivo, similar alterations of the culture conditions were unable to modify the unfavourable pattern of response to the drug in vitro. Our results indicate that the sensitivity of blast progenitors in suspension cultures strongly correlates with the remission outcome of the patients. From our data, it also appears that alterations of culture microenvironment are able to modify the response of AML blasts to Decitabine, unveiling the 'hidden' sensitivity of leukemic progenitors to the drug in cases characterized by a discrepancy between in vivo and in vitro results, i.e. apparent in vitro resistance and favourable clinical outcome.
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PMID:In vitro and in vivo effects of 5-aza-2'-deoxycytidine (Decitabine) on clonogenic cells from acute myeloid leukemia patients. 768 56

Only two classes of chemotherapeutic agents have shown activity in acute myeloid leukemia (AML): ara-C and topoisomerase II reactive agents. Frontline combinations of these agents produce complete response (CR) rates of 70% and long-term event free survival rates of 25%. New agents with different mechanisms of action are being explored. Nucleoside analogs such as chlorodeoxyadenosine (2-CdA) or fludarabine have shown single-agent efficacy and may be synergistic with ara-C. Combination therapy with ara-C and nucleoside analogs have shown promising results both as salvage therapy and in newly diagnosed patients. Combinations of topotecan with ara-C, VP16, and anthracyclines are being pursued, as is testing of other Topo-I inhibitors. Hypomethylating agents (5-azacytidine, decitabine) are showing activity in AML, producing CR rates of 5% to 30% as AML salvage therapy as a single agent, and 40%-60% in combinations. Decitabine may be synergistic with topo I inhibitors, biologic agents, and differentiating agents. Homoharringtonine has modest anti-AML activity, with CR rates of 10% to 30% as salvage therapy. Other classes of agents worthy of continuing investigation are platinum analogs and agents with novel mechanisms of action such as tallimustine.
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PMID:New chemotherapeutic agents in acute myeloid leukemia. 861 70

The aim was to determine the efficacy and safety of decitabine in the settings of relapse post-allogeneic progenitor cell transplantation or as part of the conditioning regimen. Three patients (two AML, one ALL) received single agent decitabine 1000 mg/m2 total dose) for treatment of relapse post-transplant (group 1). Median age was 32 years. Median time to relapse was 7 months. In another study four patients (three CML in an accelerated phase, one AMML) received decitabine 400 mg/m2, with busulfan 12 mg/kg and cyclophosphamide 100 mg/kg as conditioning for allogeneic stem cell transplantation (group 2). Median age was 42 years; median time to transplant was 5 months. All patients received at least 4 x 10(6) CD34+ cells from their HLA compatible donors. All patients in group 1 achieved complete remissions after decitabine therapy. The median time to neutrophil and platelet recovery were 24 and 23 days, respectively. Two patients required reinfusion of donor cells because of delayed engraftment. One patient remains alive and in remission 160 days post-decitabine therapy. Two patients in group 2 engrafted on days 23 and 25. Two patients required reinfusion of stem cells because of lack of neutrophil recovery by day 21. Two patients achieved complete cytogenetic and hematologic remission. Three patients are alive at 167,129, and 109 days post-transplant. One patient died of progressive Pseudomonas cellulitis 54 days post-initial infusion. Decitabine therapy is well tolerated in the setting of allogeneic stem cell transplantation, initial results in patients relapsing after transplant are encouraging and warrant further studies. The causes of delayed engraftment after single agent or combination therapy need to be better explored. The existence of active metabolites of decitabine which may still be present in the blood at the time of stem cell infusions, and/or insufficient immunosuppression of the preparative regimen are being explored as possible explanations for this phenomenon.
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PMID:Studies of decitabine with allogeneic progenitor cell transplantation. 913 Jun 90

The aim of the study was to evaluate the activity of decitabine, a hypomethylating agent, in the treatment of patients with chronic myelogenous leukemia (CML) in transformation. Thirty-seven patients with CML in blastic (20 patients) or accelerated phases (17 patients) were treated. Their median age was 52 years; 36 had Philadelphia chromosome-positive disease. Decitabine was given at 100 mg/m2 over 6 h every 12 h x 10 doses (1000 mg/m2) to 13 patients, and at 75 mg/m2 over 6 h every 12 h x 10 doses (750 mg/m2) to 24 patients. In blastic phase, two patients (10%) achieved a complete hematologic response (one with Ph suppression), and three (15%) had a hematologic improvement (marrow CR, platelets <100 x 10[3]/microl), for an overall response rate of 25%. In accelerated phase, six patients (35%) returned to a second chronic phase (two with Ph suppression), one (6%) had a hematologic improvement, and two (12%) had a partial hematologic response, for an overall response rate of 53%. Prolonged myelosuppression was the most significant side-effect. The median time to recovery of granulocytes above 500/microl was 48 days, and to recovery of platelets above 30 x 10(3)/microl, 31 days. Febrile episodes occurred in 25 patients (68%) including documented infections in 17 patients (46%). Decitabine has promising activity in CML. The most significant side-effect is prolonged myelosuppression. Decitabine may show activity in other myeloid disorders such as acute myeloid leukemia and myelodysplastic syndrome, as well as in other hematologic malignancies, alone or with other drug combinations. Its value in the context of stem cell support should also be investigated.
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PMID:Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. 932 79

5-Azacytidine was first synthesized almost 40 years ago. It was demonstrated to have a wide range of anti-metabolic activities when tested against cultured cancer cells and to be an effective chemotherapeutic agent for acute myelogenous leukemia. However, because of 5-azacytidine's general toxicity, other nucleoside analogs were favored as therapeutics. The finding that 5-azacytidine was incorporated into DNA and that, when present in DNA, it inhibited DNA methylation, led to widespread use of 5-azacytidine and 5-aza-2'-deoxycytidine (Decitabine) to demonstrate the correlation between loss of methylation in specific gene regions and activation of the associated genes. There is now a revived interest in the use of Decitabine as a therapeutic agent for cancers in which epigenetic silencing of critical regulatory genes has occurred. Here, the current status of our understanding of the mechanism(s) by which 5-azacytosine residues in DNA inhibit DNA methylation is reviewed with an emphasis on the interactions of these residues with bacterial and mammalian DNA (cytosine-C5) methyltransferases. The implications of these mechanistic studies for development of less toxic inhibitors of DNA methylation are discussed.
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PMID:5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. 1215 9

Decitabine [NSC 127716, DAC, dezocitidine, Aza dC, 2'-deoxy-5-azacytidine] is a deoxycytidine and cytarabine derivative with potent antileukaemic activity, which was originated by Pharmachemie. This antimetabolite is able to induce in vitro gene activation and cellular differentiation by a mechanism involving DNA hypomethylation. SuperGen acquired worldwide rights to decitabine from Pharmachemie in the third quarter of 1999 for 4 million US dollars worth of SuperGen shares and income from manufacture upon the launch of decitabine. SuperGen announced in May 2000 that it had entered a Cooperative Research and Development Agreement (CRADA) with the US National Cancer Institute (NCI). SuperGen will supply decitabine to the NCI, which will initiate and sponsor clinical trials in patients with solid tumours and haematological malignancies. The NCI will also conduct studies on decitabine's mechanism of action. In 2002, the US FDA has granted decitabine orphan drug status for the treatment of myelodysplastic syndromes and sickle cell anaemia. In February 2003, the European Commission granted orphan drug status to decitabine for myelodysplastic syndrome. Decitabine has also received orphan drug status in the US as a host-protective agent in the treatment of AML. Decitabine has been studied in solid tumours as well as in different types of leukaemia. In several phase II studies it has been shown to have very limited efficacy against solid tumours. However, decitabine has shown better activity in the treatment of haematological malignancies such as acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and myelodysplastic syndrome (preleukaemia). In March 2001, SuperGen announced that it had begun patient enrolment into its pivotal open-label phase III trial of decitabine in advanced myelodysplastic syndrome patients. The study, which will compare decitabine with standard care therapy, will be conducted at 15 medical centres in the US and will enrol a total of 160 patients. In March 2003, SuperGen announced that patient enrolment was complete. The study, which will compare decitabine with standard care therapy, will be conducted at 22 medical centres in the US and will enrol a total of 160 patients. A European pivotal trial is also underway for the same indication, and is aiming to enrol 220 patients. A phase I/II trial of 8 patients, designed to establish safety and efficacy in the treatment of sickle cell anaemia, has been completed at the University of Illinois, USA. Plans for additional studies of decitabine as a treatment for sickle cell anaemia are underway. Decitabine is also undergoing phase II clinical trials in Canada, for the treatment of non-small cell lung cancer, and in the US for chronic myeloid leukaemia and prostate cancer. Glasgow University in Scotland has conducted preclinical trials in chemotherapy-resistant ovarian and colon cancers. The results suggest that decitabine administration may reverse chemotherapy resistance in these cancers. SuperGen was issued a US patent (No. 6 191 119) in 2001 covering the use of decitabine in combination with rubitecan and antibiotic agents, including doxorubicin.
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PMID:Decitabine: 2'-deoxy-5-azacytidine, Aza dC, DAC, dezocitidine, NSC 127716. 1275 5

DNA methylation abnormalities have recently emerged as one of the most frequent molecular changes in hematopoietic neoplasms. Since methylation and transcriptional status are inversely correlated, the hypermethylation of genes involved in cell-cycle control and apoptosis could have a pathogenetic role in the development of cancer. In particular, high-risk myelodysplastic syndromes (MDS) and secondary leukemias show a high prevalence of tumor suppressor gene hypermethylation. The progression of chronic myeloproliferative diseases and of myelodysplastic syndromes, as well as that of lymphoproliferative diseases, is associated with an increased methylation rate, pointing to a role for hypermethylation of critical promoter regions in the transformation to more aggressive phenotypes. In the same line, a significantly worse prognosis has been shown for patients with hypermethylation of several genes compared to that of patients with unmethylated genes. For these reasons, the use of irreversible DNA methyltransferase inhibitors, such as 5-azacytidine and Decitabine, appears to be a promising option for the treatment of MDS and acute myeloid leukemia. In clinical trials, Azacytidine results in a significantly higher response rate, improved quality of life, reduced risk of leukemic transformation, and improved survival compared to supportive care. Similarly, Decitabine showed favorable results, promising response rates, a good nonhematologic toxicity profile, and a trend for better survival compared to intensive chemotherapy, particularly in older patients. The synergistic effect of histone deacetylase inhibitors, including phenylbutyrate (PB), in reactivating silenced genes encouraged clinical studies on the combination of PB and demethylating agents in hematological diseases, characterized by p15 silencing. The sequential administration of a "first generation" demethylating agent and HDAC inhibitors gave preliminary evidence of a reduced methylation of target genes, as also described with Decitabine. Clinical trials are still ongoing, and preliminary data indicate for the first time that the natural history of MDS may be changed by a non-intensive treatment, characterized by an outstanding toxicity profile.
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PMID:Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. 1458 80

Decitabine (5-aza-2'-deoxycytidine) inhibits DNA methylation and has dual effects on neoplastic cells, including the reactivation of silenced genes and differentiation at low doses and cytotoxicity at high doses. We evaluated, in a phase 1 study, low-dose prolonged exposure schedules of decitabine in relapsed/refractory leukemias. Patient cohorts received decitabine at 5, 10, 15, or 20 mg/m2 intravenously over one hour daily, 5 days a week for 2 consecutive weeks, doses 5- to approximately 30-fold lower than the maximum tolerated dose (MTD). There were 2 groups that also received 15 mg/m2 daily for 15 or 20 days. A total of 50 patients were treated (44 with acute myelogenous leukemia [AML]/myelodysplasia [MDS], 5 with chronic myelogenous leukemia [CML], and 1 with acute lymphocytic leukemia [ALL]), and the drug was well tolerated at all dose levels, with myelosuppression being the major side effect. Responses were seen at all dose levels. However, the dose of 15 mg/m2 for 10 days appeared to induce the most responses (11 of 17 or 65%), with fewer responses seen when the dose was escalated or prolonged (2 of 19 or 11%). There was no correlation between P15 methylation at baseline or after therapy and response to decitabine. We conclude that decitabine is effective in myeloid malignancies, and low doses are as or more effective than higher doses.
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PMID:Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. 1460 77

Normal cell development and function is dependent upon controlled gene expression. DNA methylation is an epigenetic modification that can play an important role in the control of gene expression. DNA methylation at cytosine residues in gene promoter CpG sequences is known to inhibit gene transcription. Inappropriate inhibition of the transcription of tumour suppressor genes, genes that inhibit angiogenesis and metastasis and genes involved in DNA repair by uncontrolled methylation, can lead to unregulated growth and proliferation of a cell and carcinogenesis. Promoter hypermethylation affecting the p16 gene, resulting in gene silencing, has been shown to occur in many human solid tumours and a 'hypermethylation profile' in some leukaemias has been defined. The molecular mechanisms by which aberrant DNA methylation takes place during carcinogenesis are still not clear. However, the large number of target genes (involved in tumorigenesis) that are silenced by aberrant methylation suggests that inhibition of this process may have potential as cancer therapy. Decitabine (NSC-127716, Dacogen; SuperGen) is a potent and specific hypomethylating agent and an inhibitor of the DNA methyltransferase activity that mediates DNA methylation. Decitabine has been shown to have a broad range of antineoplastic activity in preclinical studies. This agent has exhibited significant activity in the treatment of patients with myelodysplastic syndrome, chronic myeloid leukaemia and acute myeloid leukaemia, although clinical Phase I and II studies with solid tumours have not been very promising. Phase II and III studies are currently ongoing to evaluate decitabine, both alone and in combination, in various stages of these haematological malignancies.
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PMID:DNA methylation in haematological malignancies: the role of decitabine. 1464 Sep 42

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