Low-Dose 5-Aza-2′-Deoxycytidine, a DNA Hypomethylating Agent, for the Treatment of High-Risk Myelodysplastic Syndrome: A Multicenter Phase II Study in Elderly Patients

Wijermans, Pierre W.; Lübbert, Michael; Verhoef, Gregor; Bosly, André; Ravoet, Christophe; André, Marc; Ferrant, Augustin

doi:10.1200/jco.2000.18.5.956

Cited by 529 publications

(298 citation statements)

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“…While other methylation inhibitors like zebularine are known, most data are available for 5-Aza-CdR in terms of its clinical utility. Two phase II clinical studies have reported promising therapeutic activity of 5-Aza-CdR (decitabine) for patients with MDS 3 or CML. 4 Two other studies, enrolling mostly patients with AML, reported good response rates after decitabine treatment.…”

mentioning

confidence: 99%

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

Schmelz

Wagner

Dörken

et al. 2005

Intl Journal of Cancer

106

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The DNA methylation inhibitor 5-Aza-2 -deoxycytidine (5-AzaCdR) has significant therapeutic value for the treatment of patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The demethylating effect of 5-Aza-CdR has been well characterized. In contrast, less is known about the molecular events downstream of the methylation inhibition. Here, 5-Aza-CdR induced apoptosis in AML cells (both p53 mutant and wild-type) but not in epithelial or normal PBMCs. Cell death was accompanied by activation of the mitochondrial apoptosis pathway, as shown by release of cytochrome c and AIF and loss of mitochondrial membrane potential (⌬⌿m). Activation of caspase-3 (but not ؊6 and ؊8) was detectable using Western blot analysis and measurement of caspase enzymatic activity. 5-Aza-CdR treatment resulted in the induction of p21, which correlated with the arrest of AML cells in the G 1 cell cycle phase. Induction of p21 expression was independent of its promoter methylation status but mediated by 5-Aza-CdR-induced reexpression of the tumor-suppressor p73, a known upstream regulator of p21. The p73 promoter was hypermethylated in AML cell lines and in primary AML cells but not in epithelial cells, which were resistant toward 5-Aza-CdR. Therefore, 5-Aza-CdRmediated specific killing of myeloid cells might be dependent on its ability to revert p73 promoter methylation and to reexpress p73 mRNA. In addition, exogenous expression of p73 rendered epithelial cells sensitive to apoptosis induced by 5-Aza-CdR or other cytostatic drugs. We therefore conclude that p73 is a relevant target for methylation-dependent efficacy of 5-Aza-CdR in AML cells.Key words: 5-aza-2Ј-deoxycytidine; p21 WAF ; p73; p53; myeloid leukemia; DNA methylation DNA methylation is an epigenetic mechanism of gene regulation that plays a crucial role in carcinogenesis due to silencing of cancer-related genes. 1 Transcriptional blockage occurs as a consequence of methylated CpG islands in the 5Ј region of genes, which is mediated by DNMTs during DNA replication. 2 In contrast to gene mutation, DNA methylation is a reversible event open to attack by DNA methylation inhibitors like 5-Aza-CdR. As a nucleoside analogue, 5-Aza-CdR is integrated into DNA and inhibits DNA methylation by trapping DNMTs. While other methylation inhibitors like zebularine are known, most data are available for 5-Aza-CdR in terms of its clinical utility. Two phase II clinical studies have reported promising therapeutic activity of 5-Aza-CdR (decitabine) for patients with MDS 3 or CML. 4 Two other studies, enrolling mostly patients with AML, reported good response rates after decitabine treatment. 5,6 5-Aza-CdR effectively reverts methylation-dependent gene repression, as shown, e.g., for p15 INK4b in vitro and in vivo. 6 In AML cells, promoter hypermethylation has been reported for several other genes, including the estrogen receptor, E-cadherin 7 HIC1, calcitonin 8 and MYOD. 9 The molecular effects of 5-Aza-CdR can include histone deacetylation a...

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mentioning

confidence: 99%

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

Schmelz

Wagner

Dörken

et al. 2005

Intl Journal of Cancer

106

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“…In a multicenter, Phase II study, Wijermans et al treated 66 elderly patients (median age, 66 years) with decitabine 45 mg/m 2 daily (15mg/m 2 intravenously over 4 hours every 8 hours) for 3 days every 6 weeks. 104 Twenty-five patients had high IPSS risk scores. Overall, 49% of patients responded (CR, 20%; PR, 4%; hematologic improvement, 24%), and the response rate was 64% in the high-risk group.…”

Section: Epigenetic Therapymentioning

confidence: 99%

Novel therapies for myelodysplastic syndromes

Faderl

Kantarjian

2004

Cancer

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BACKGROUND.The assessment of patients with myelodysplastic syndromes (MDS) and the choice of therapies remain challenging. New therapies are now emerging after the identification of molecular targets that result in improvement of hematologic parameters and may hold promise for the prevention of disease progression. METHODS.A review of the English literature was performed that included original articles and related reviews from MEDLINE (PubMed) and abstracts based on published meeting material. RESULTS.MDS is a heterogeneous group of disorders. Although current classification and prognostic schemes have proven valid to define subgroups, they are insufficient to take into consideration the significant biologic diversity of MDS.

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“…27 Decitabine has been investigated in elderly patients with MDS. 28 In a study of 66 patients with MDS, decitabine was administered at a dose of 45 mg/m 2 per day for 3 days every 6 weeks for a maximum of 6 cycles. 28 The overall response rate was 49%.…”

Section: Hypomethylating Agents (Decitabine and 5-azacytidine)mentioning

confidence: 99%

“…28 In a study of 66 patients with MDS, decitabine was administered at a dose of 45 mg/m 2 per day for 3 days every 6 weeks for a maximum of 6 cycles. 28 The overall response rate was 49%. Patients who had an International Prognostic Scoring System (IPSS) high-risk score had a response rate of 64%.…”

Section: Hypomethylating Agents (Decitabine and 5-azacytidine)mentioning

confidence: 99%

“…The median response duration was 31 weeks, the median survival from diagnosis was 22 months, and the median survival from the start of therapy was 15 months. 28 Disappearance of chromosomal abnormalities that were present before the initiation of therapy and reversal of hypermethylation were observed in responding patients. 29 31 Ongoing studies include a randomized, multicenter study comparing decitabine with supportive care in patients with MDS and other studies investigating alternative schedules and subcutaneous route of administration in patients with MDS, AML, and CML after failure to imatinib mesylate.…”

Section: Hypomethylating Agents (Decitabine and 5-azacytidine)mentioning

confidence: 99%

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New agents in acute myeloid leukemia and other myeloid disorders

Ravandi

Kantarjian

Giles

et al. 2004

Cancer

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Low-Dose 5-Aza-2′-Deoxycytidine, a DNA Hypomethylating Agent, for the Treatment of High-Risk Myelodysplastic Syndrome: A Multicenter Phase II Study in Elderly Patients

Abstract: We were able to confirm our previous observation that DAC therapy was effective in half of the studied patients with high-risk myelodysplastic syndrome and is especially active in the patients with the worst prognoses. Myelosuppression was the only major adverse effect observed.

Cited by 529 publications

References 19 publications

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

Novel therapies for myelodysplastic syndromes

New agents in acute myeloid leukemia and other myeloid disorders

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Low-Dose 5-Aza-2′-Deoxycytidine, a DNA Hypomethylating Agent, for the Treatment of High-Risk Myelodysplastic Syndrome: A Multicenter Phase II Study in Elderly Patients

Abstract: We were able to confirm our previous observation that DAC therapy was effective in half of the studied patients with high-risk myelodysplastic syndrome and is especially active in the patients with the worst prognoses. Myelosuppression was the only major adverse effect observed.

Cited by 529 publications

References 19 publications

5‐Aza‐2′‐deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

5‐Aza‐2′‐deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

Novel therapies for myelodysplastic syndromes

New agents in acute myeloid leukemia and other myeloid disorders

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Product

Resources

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5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia

5‐Aza‐2′‐deoxycytidine induces p21^WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia