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)

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

Decitabine [NSC 127716, DAC, dezocitidine, Aza dC, 2'-deoxy-5-azacytidine, Dacogen( trade mark )] is a deoxycytidine and cytarabine derivative with potent antileukaemic activity, originated by Pharmachemie. This antimetabolite is able to induce in vitro gene activation and cellular differentiation by a mechanism involving DNA hypomethylation. Decitabine has been studied in several phase II trials for solid tumours as well as in different types of leukaemia. The drug has been shown to have very limited efficacy against solid tumours. However, decitabine exhibits higher activity for the treatment of haematological malignancies. SuperGen announced that it had entered a Cooperative Research and Development Agreement (CRADA) with the US National Cancer Institute (NCI) in May 2000. 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. SuperGen had previously 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. The drug is undergoing two phase II trials for the treatment of cytomegalovirus leukaemia (CML) in the US, one of which will assess the safety, response rate, duration of response, and survival of decitabine (injection) in combination with imatinib mesylate (oral). SuperGen initiated a phase II clinical study of decitabine in combination with imatinib mesylate in June 2003 that will be conducted under SuperGen's CRADA with the National Cancer Institute and will take place at the MD Anderson Cancer Center in the US. Approximately 80 patients with CML will be enrolled in the study. This followed on decitabine's orphan drug status for the same indication, which was granted by the US FDA in 2002. In addition, the European Commission has granted orphan drug status to decitabine for MDS treatment in February 2003. In March 2003, SuperGen announced that patient enrolment was completed for its open-label, phase III trial comparing decitabine with standard care therapy for treatment of advanced myelodysplastic syndrome, which was initiated in March 2001. The study will be conducted at 22 medical centres in the US and will enrol a total of 160 patients. A pivotal trial is also underway in Europe for the same indication and is aiming to enrol 220 patients. In addition, decitabine is undergoing phase II trials for the treatment of non-small cell lung cancer (NSCLC) in Canada and for prostate cancer in the US. In July 2003, SuperGen was issued a US patent relating to decitabine as part of a combination therapy with other anticancer agents to treat ovarian, breast, prostate, gastric, lung, pancreatic and colon cancers through the correction of DNA hypermethylation. 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. 1458 64

Decitabine (DAC) is a small molecule nucleotide analog that is incorporated into DNA and traps human DNA methyltransferases. Although initially developed as a cytotoxic agent, low-dose DAC is enjoying a revival as a specific inhibitor of hypermethylation in cancer. DAC has activity in several hematological diseases, especially myelodysplastic syndrome, chronic myelogenous leukemia and acute myeloid leukemia. Clinical and preclinical advances are presented in this review.
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PMID:Decitabine: development of a DNA methyltransferase inhibitor for hematological malignancies. 1476 30

To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1-3; cytarabine (AraC) 200 mg/m2/day, days 1-7; cladribine (2-CdA) 5 mg/m2/day, days 1-5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16-60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.
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PMID:Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. 1499 98

The demethylating agents 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine at low doses induce hematologic and cytogenetic remissions in a subset of patients with MDS. It is unclear whether the correction of neutropenia involves differentiation of abnormal granulocyte precursors, or emergence of normal granulopoiesis. A previous study in three MDS patients, analyzing a differentiating activity of GM-CSF, had shown heterogenous granulocyte responses. The objective of our study was to determine the ratio of clonal and nonclonal peripheral blood granulocytes in MDS patients treated with DAC using FISH analysis. In two patients with initial severe neutropenia, an informative cytogenetic marker, complete normalization of peripheral blood neutrophils and a bone marrow cytogenetic response following DAC, >90% of the cells contributing to neutrophil normalization lacked this clonal marker. In one of them, an early and transient increase in clonal neutrophils was compatible also with a modest differentiating effect upon the dysplastic granulocyte precursors, whereas in a third patient, resistant to re-treatment with DAC, no expansion of either granulocyte population occurred. In the responders, leukocyte nadirs following DAC appeared less pronounced after conversion to normal cytogenetics. In conclusion, restoration of nonclonal hematopoiesis may be the predominant effect of DAC both in early and late stages of treatment, at least in patients achieving a hematologic and cytogenetic response.
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PMID:Nonclonal neutrophil responses after successful treatment of myelodysplasia with low-dose 5-aza-2'-deoxycytidine (decitabine). 1547 67

In several large phase II trials, low-dose treatment with the azanucleoside 5-aza-2'-deoxycytidine (decitabine, DAC) resulted in complete hematologic and cytogenetic responses in 23 and 31% of MDS patients, respectively. The question of induction of chromosomal instability by this demethylating agent was addressed by serial karyotypic analyses. 53/122 DAC-treated patients had all normal metaphases at time of treatment start. In 46/53 patients, sequential cytogenetic analyses were performed. 9/46 patients (20%) acquired clonal chromosomal abnormalities during follow-up (4/9 transient). 8/9 abnormalities were gains or losses of entire chromosomes. The rate and pattern of cytogenetic evolution are thus not higher than in historical MDS cohorts not receiving specific treatment.
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PMID:Treatment of myelodysplastic syndrome with a DNA methyltransferase inhibitor: lack of evidence for induction of chromosomal instability. 1616 57

Although the first studies using DNA demethylating agents at low doses in hematologic neoplasia and hemoglobinopathies were initiated more than 20 years ago, development of this type of nonintensive treatment has only been spurred in the last 6 to 8 years by the discovery of many genes that are specifically hypermethylated in cancer. These provide a powerful rationale for using azanucleosides (and other small molecules being developed for DNA demethylation) as a novel means of pharmacologic targeting of cancer cells that is distinct from low-dose chemotherapy. Encouraging response rates of about 50% in myelodysplasia with 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine or DAC) have resulted in a number of phase III studies being initiated in this disorder. The development of such drugs for the treatment of acute myeloid leukemia (AML) is ongoing. While the specificity of DNA demethylation has been delineated by studying distinct genes or sets of genes, and proof-of-principle studies of in vivo methylation report demethylation and reactivation of genes like p15/INK4b and gamma-globin, responses to demethylating agents may be more complex. Specifically, so-called cancer testis antigens (CTAs) are intriguing targets for demethylation, since they are silenced in many hematopoietic disorders and may be reactivated by epigenetic therapy. Thus, demethylating agents and histone deacetylase inhibitors may also induce a T-cell-mediated antileukemic or antitumor effect.
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PMID:Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents. 1621 92

During the last 10 years, three European phase II studies were performed to investigate the treatment of elderly patients with myelodysplastic syndrome (MDS) with low-dose 5-aza-2'-deoxycytidine (decitabine, DAC). All these European trial data were reviewed on the basis of the International Prognostic Scoring System (IPSS) risk criteria and the response criteria as recently published by an international working group. To investigate the results in a larger cohort of patients and to determine risk factors, all data were pooled with some observations from the PCH 95-06 US phase II study. The response rate in the 177 patients evaluated (median age 70 years) was 49%. The median response duration was 36 weeks, and the median survival was 15 months. Analysis of the data according to sex, age, French-American-British classification, percentage of blasts in the bone marrow, IPSS risk group, lactate dehydrogenase and cytogenetics did not reveal any factor predictive of response. Overall, 69% of patients benefited, including those with stable disease during therapy. Response duration was significantly shorter with increasing risk (according to the IPSS classification). Haemoglobin level and neutrophil count showed an inverse correlation to the IPSS classification. Univariate analysis showed a significantly inferior survival for elderly patients (>75 years of age) and for those with high levels of serum lactate dehydrogenase (LDH) (more than two times the normal values). Patients with high-risk cytogenetic abnormalities according to the IPSS risk criteria showed better overall survival than those with intermediate-risk abnormalities. When analysed according to the IPSS risk classification, high-risk patients had worse survival prospects following decitabine therapy than those with intermediate risk; however, compared to the originally reported IPPS outcomes for high-risk patients, they probably showed better survival. During the treatment period, 18% of the patients progressed towards acute leukaemia. Decitabine showed a rather low toxicity profile in this elderly patient group. In conclusion, low-dose decitabine is an active drug for the treatment of MDS patients, even for those older than 75 years with bad prognostic characteristics.
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PMID:An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients. 1621 86

Recent evidence demonstrates that epigenetic silencing of genes is associated with myelodysplasia and that a worse prognosis may be correlated with hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor p15. 5-Aza-2'-deoxycytidine (decitabine, DAC) is a nucleoside analog, which, at low doses, acts as a hypomethylating agent and is fivefold to tenfold more active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have demonstrated that decitabine has activity in patients with MDS. Preliminary results of a phase III multicenter North American trial comparing low-dose decitabine to supportive care verified that therapy with decitabine resulted in higher response rates, improved quality of life, and prolonged time to leukemic transformation and/or death. However, further elucidation of its mechanism of action is required, as clinical response to decitabine does not correlate with demethylation of the p15 gene promoter or the repetitive DNA element LINE. Decitabine appears to upregulate both hypermethylated and nonmethylated genes. Ongoing studies aim to determine the optimal dose, schedule, and route of administration of decitabine, and to evaluate whether efficacy can be improved by using it in combination with other agents, such as histone deacetylase inhibitors.
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PMID:Clinical experience with decitabine in North American patients with myelodysplastic syndrome. 1627 8

Low-dose demethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) and 5-azacytidine (azacitidine, Vidaza) have been explored for the treatment of myelodysplasia, acute myeloid leukemia, and hemoglobinopathies since the early 1980s, aiming to revert a methylator phenotype. Originally, the treatment rationale in hemoglobinopathies was to achieve demethylation of the hypermethylated and hence silent gamma-globin gene locus, thus reactivating synthesis of hemoglobin F (HbF). In myelodysplastic syndrome (MDS), cytogenetic analyses are mandatory for risk stratification and for monitoring response to drug treatment. The current knowledge regarding cytogenetic subgroups as predictors of response to low-dose decitabine in MDS as well as cytogenetic responses caused by demethylating agents is summarized in this review. Decitabine treatment is associated with a response rate that is higher in patients with high-risk cytogenetics (i.e., complex karyotype and/or abnormalities of chromosome 7) than in patients with intermediate-risk cytogenetics (two abnormalities or single abnormalities excluding 5q-, 20q-, and -Y). Following decitabine treatment of patients with abnormal karyotype, approximately one-third achieve a major cytogenetic response that can be confirmed by FISH analyses, while in two-thirds of patients, the abnormal karyotype persists but hematologic improvement may be observed during continued treatment. The most frequently studied gene in myelodysplasia is the cell cycle regulator p15(INK4b). Hypermethylation of p15(INK4b) in MDS is reversed during treatment with decitabine, resulting in reactivation of this gene. In hemoglobinopathies, treatment with demethylating agents leads to reactivation of fetal HbF (the gamma-globin gene locus also possibly being another target for reactivation in MDS), and thus, HbF may potentially act as surrogate marker for activity of decitabine. Other, thus far unidentified hypermethylated genes may also be targets for demethylating agents.
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PMID:In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies. 1629 49


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