Induction of differentiation and inhibition of DNA methylation in HL-60 myeloid leukemic cells by 5-AZA-2′-deoxycytidine

Momparler, Richard L.; Bouchard, Jacques; Samson, Johanne

doi:10.1016/0145-2126(85)90123-7

Cited by 66 publications

(38 citation statements)

References 13 publications

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“…The antitumoral activity of decitabine was evaluated in vitro in several leukemic cell lines and solid tumors, where the 50% inhibitory concentration ranged from 10 nM to 10 mM. Concentrations of decitabine optimal to induce DNA hypomethylation reached a plateau above concentrations of 0.5 mM to 1 mM, whereas higher concentrations increased cytotoxicity [16][17][18][19].…”

Section: Nonclinical Aspects and Clinical Pharmacologymentioning

confidence: 99%

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

et al. 2016

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On September 20, 2012, a marketing authorization valid throughout the European Union (EU) was issued for decitabine for the treatment of adult patients aged 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy. Decitabine is a pyrimidine analog incorporated into DNA, where it irreversibly inhibits DNA methyltransferases through covalent adduct formation with the enzyme.The use of decitabine was studied in an open-label, randomized, multicenter phase III study (DACO-016) in patients with newly diagnosed de novo or secondary AML. Decitabine (n 5 242) was compared with patient's choice with physician's advice (n 5 243) of low-dose cytarabine or supportive care alone. The primary endpoint of the study was overall survival. The median overall survival in the intent-to-treat (ITT) population was 7.7 months among patients treated with decitabine compared with 5.0 months for those in the control arm (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.04; p 5 .1079). Mature survival data after an additional year of follow-up were consistent with these results, with a median overall survival of 7.7 months in patients treated with decitabine and 5.0 months in the control arm (HR, 0.82; 95% CI, 0.68-0.99; p 5 .0373). Secondary endpoints, including response rates, progressionfree survival, and event-free survival, were increased in favor of decitabine when compared with control treatment. The most common adverse drug reactions reported during treatment with decitabine are pyrexia, anemia, thrombocytopenia, febrile neutropenia, neutropenia, nausea, and diarrhea. This paper summarizes the scientific review of the application leading to approval of decitabine in the EU. The detailed scientific assessment report and product information (including the summary of product characteristics) for this product are available on the EMA website (http://www.ema.europa.eu). The Oncologist 2016;21:692-700

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Section: Nonclinical Aspects and Clinical Pharmacologymentioning

confidence: 99%

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

et al. 2016

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“…5aza-dC is widely used to reactivate the expression of genes silenced by methylation (Heller et al, 2010). It has also been shown to induce cellular differentiation (Taylor and Jones, 1979;Momparler et al, 1985). Genes that were significantly upregulated in at least four cell lines after treatment were considered to be hypermethylated and were mapped onto the four DTs (Figure 4).…”

Section: Go Analysismentioning

confidence: 99%

DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

2011

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Aberrant DNA hypermethylation of tumor suppressor genes is thought to be an early event in tumorigenesis. Many studies have reported the methylation status of individual genes with known involvement in cancer, but an unbiased assessment of the biological function of the collective of hypermethylated genes has not been conducted so far. Based on the observation that a variety of human cancers recapitulate developmental gene expression patterns (that is activate genes normally expressed in early development and suppress late developmental genes), we hypothesized that the silencing of differentiation-associated genes in cancer could be attributed in part to DNA hypermethylation. To this end, we investigated the developmental expression patterns of genes with hypermethylated CpG islands in primary human lung carcinomas and lung cancer cell lines. We found that DNA hypermethylation primarily affects genes that are expressed in late stages of murine lung development. Gene ontology characterization of these genes shows that they are almost exclusively involved in morphogenetic differentiation processes. Our results indicate that DNA hypermethylation in cancer functions as a selective silencing mechanism of genes that are required for the maintenance of a differentiated state. The process of cellular de-differentiation that is evident on both the microscopic and transcriptional level in cancer might at least partly be mediated by these epigenetic events. Our observations provide a mechanistic explanation for induction of differentiation upon treatment with DNA methyltransferase inhibitors.

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“…As early as the 1980s, decitabine was found to possess ROSgenerating characteristics in AML cell lines (74). At the time, this was attributed to an effect on differentiation, because a myeloid cell line was used, and it was assumed that differentiation of these cells would enable a functional NADPH oxidase.…”

Section: Fig 5 Proteasome Inhibitors Can Promote An Antioxidant Resmentioning

confidence: 99%

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Chandra

2009

Antioxidants & Redox Signaling

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The past decade has seen an exponential increase in the number of cancer therapies with defined molecular targets. Interestingly, many of these new agents are also documented to raise levels of intracellular reactive oxygen species (ROS) in addition to inhibiting a biochemical target. In most cases, the exact link between the primary target of the drug and effects on cellular redox status is unknown. However, it is important to understand the role of oxidative stress in promoting cytotoxicity by these agents, because the design of multiregimen strategies could conceivably build on these redox alterations. Also, drug resistance mediated by antioxidant defenses could potentially be anticipated and circumvented with improved knowledge of the redoxrelated effects of these targeted agents. Given the large number of targeted chemotherapies, in this review, we focus on selected agents that have shown promise in hematologic malignancies: proteasome inhibitors, histone deacetylase inhibitors, Bcl-2-targeted agents, and a kinase inhibitor called adaphostin. Despite structural differences within classes of these compounds, a commonality of causing increased oxidative stress exists, which contributes to induction of cell death. Antioxid. Redox Signal. 11, 1123-1137.

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Induction of differentiation and inhibition of DNA methylation in HL-60 myeloid leukemic cells by 5-AZA-2′-deoxycytidine

Cited by 66 publications

References 13 publications

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

DNA hypermethylation in lung cancer is targeted at differentiation-associated genes

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

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