Disease relevance of Decitabine

• Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC) [1].
• Effects of 5-aza-2'-deoxycytidine on matrix metalloproteinase expression and pancreatic cancer cell invasiveness [2].
• Toxicity of 5-aza-2'-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation [3].
• Its expression was restored by treatment with 5-aza-2'-deoxycytidine in 11 of 14 cell lines with reduced MYO18B expression, and the promoter CpG island of the MYO18B gene was methylated in 17% (8/47) of lung cancer cell lines and 35% (14/40) of primary lung cancers [4].
• Hypermethylation of final sigma is functionally important, because treatment of final sigma-non-expressing breast cancer cell lines with the drug 5-aza-2'-deoxycytidine resulted in demethylation of the gene and synthesis of final sigma mRNA [5].

High impact information on Decitabine

• The transcriptional silencing in ros1 mutants can be released by the ddm1 mutation or the application of the DNA methylation inhibitor 5-aza-2'-deoxycytidine [6].
• We tested this model by using the potent methylation inhibitor 5-aza-2'-deoxycytidine (5adc) to hypomethylate parental cpDNA and found that the pattern of cpDNA inheritance is altered by 5adc in a manner that is consistent with the model [7].
• The DNA methylase inhibitor, 5-aza-2'-deoxycytidine, induced KIR DNA hypomethylation and heterogeneous expression of multiple KIR genes [8].
• Treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine restored IL-12Rbeta2 mRNA expression in primary neoplastic B cells that underwent apoptosis following exposure to human recombinant IL-12 (hrIL-12). hrIL-12 inhibited proliferation and increased the apoptotic rate of IL-12Rbeta2-transfected B cell lines in vitro [9].
• Silenced tumor suppressor genes are obvious targets for reactivation by methylation inhibitors such as 5-azacytidine (5-Aza-CR) and 5-aza-2'-deoxycytidine (5-Aza-CdR) [10].

Chemical compound and disease context of Decitabine

• We have previously demonstrated that 5-aza-2'-deoxycytidine (decitabine) augments fetal hemoglobin (HbF) levels in patients with sickle cell anemia (SS) who did not respond to hydroxyurea (HU) [11].
• In pancreatic cancer cell lines that retained methylation of 1 or more of the 7 aforementioned overexpressed and hypomethylated genes, treatment with 5-aza-2'-deoxycytidine or with trichostatin A, either alone or in combination, almost invariably reactivated the transcription of each of these 7 genes [12].
• Azanucleoside drugs such as 5-azacytidine (Vidaza) and 5-aza-2'-deoxycytidine (decitabine, Dacogen) function as DNA methyltransferase inhibitors in vitro and represent promising new drugs for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia [13].
• To identify methylation-mediated silencing of genes in hepatocellular carcinoma (HCC), we surveyed genes induced by treatment with 5-aza-2'-deoxycytidine (5-Aza-CdR) in six human hepatoma cell lines using cDNA microarray analysis and determined the methylation status of 5' CpG islands by bisulfite DNA sequencing or methylation-specific PCR [14].
• The purpose of this study was to compare the frequency of generation and in vivo cross-reactivity of highly immunogenic (Imm+) clones induced in a single parental murine fibrosarcoma cell line MCA-F by 4 weekly treatments with either UV-B radiation, 1-methyl-3-nitro-1-nitrosoguanidine, or 5-aza-2'-deoxycytidine [15].

Biological context of Decitabine

• Four tumor lines with methylated promoter regions lacked expression of these isoforms, but demethylation by exposure to 5-aza-2'-deoxycytidine restored their expression [16].
• Progressive stages of "transdifferentiation" from epidermal to mesenchymal phenotype induced by MyoD1 transfection, 5-aza-2'-deoxycytidine treatment, and selection for reduced cell attachment in the human keratinocyte line HaCaT [17].
• To gain insight into how 5-aza-2'-deoxycytidine induces mutations in vivo, we examined the mutational spectrum in an Escherichia coli lac I transgene in colonic DNA from 5-aza-2'-deoxycytidine-treated mice [18].
• The inactive X chromosome present in the hybrid, was found to be late replicating, and experiments with synchronized cells showed that the induction of HPRT expression by 5-aza-2'-deoxycytidine occurred maximally in cells treated in the latter half of the S phase [19].
• We describe here another example of an XIST-expressing human-hamster hybrid that lacks X-linked gene repression in which the human XIST gene present on an active X chromosome was reactivated by treatment with 5-aza-2'-deoxycytidine [20].

Anatomical context of Decitabine

• However, 7 days following 5-aza-2'-deoxycytidine treatment, the incorporation of dThd into DNA in the spleens of mice was significantly increased [21].
• 5-Aza-2'-deoxycytidine is a highly effective cytostatic agent that preferentially affects the lymphatic system [21].
• Treatment with the demethylating agent 5-aza-2'-deoxycytidine activated gene MAGE-1 not only in tumor cell lines but also in primary fibroblasts [22].
• Immunohistochemical staining for p15 protein in bone marrow biopsies from 8 patients with p15 hypermethylation revealed low or absent expression in 4 patients, which was induced to normal levels during decitabine treatment [23].
• Demethylation by treatment of hypermethylated K562 cells with 5-aza-2'-deoxycytidine resulted in partial reactivation of JunB expression [24].

Associations of Decitabine with other chemical compounds

• Growth of B. napus seedlings on 5-aza-2'-deoxycytidine to inhibit cytosine methylation caused the normally silent, under-dominant B. oleracea rRNA genes to become expressed to high levels [25].
• Last, sequential treatment with 5-aza-2'-deoxycytidine followed by zebularine hindered the remethylation of the p16 5' region and gene resilencing, suggesting the possible combination use of both drugs as a potential anticancer regimen [26].
• The AraC-resistant rat leukemic cell line RO/1-A has been shown to have a typical deoxycytidine kinase (DCK)-deficient phenotype and cannot metabolize the antileukemic drugs cytarabine (AraC) and decitabine (DAC) [27].
• Furthermore, the association of methylated lysine 9 on histone H3, a hallmark of promoter methylation, with the promoter was reduced following 5-aza-dC treatment [28].
• Treatment of SUSM-1 cells with the demethylating agent 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor trichostatin A induced the cells to express hTERT, suggesting a potential role for DNA methylation and/or histone deacetylation in negative regulation of hTERT [29].
• Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy [30].

Gene context of Decitabine

• Exposure of cells to histone deacetylase inhibitors, or to the demethylating agent 5-aza-2'-deoxycytidine, revealed that HLA-G gene transcription is inhibited by DNA methylation [31].
• The five remaining cell lines had a partially methylated CDX1 promoter and all expressed CDX1 mRNA; when treated with the demethylating agent, 5-aza-2'-deoxycytidine, these five cell lines all showed increased CDX1 expression [32].
• We used an antibody-based method to identify specific endogenous DNMTs (DNMT1, DNMT1b, DNMT2, DNMT3a, and DNMT3b) that stably and selectively bind to genomic DNA containing 5-aza-2'-deoxycytidine (aza-dC) in vivo [33].
• In one of these situations, ARF transcription could be reactivated by treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine, and the reactivation kinetics of ARF and INK4a were found to differ slightly in a cell line in which both genes were silenced by methylation [34].
• On the silent allele, 5-aza-dC treatment altered SNRPN expression, but not association with acetylated histones, suggesting that histone acetylation is a secondary event in the process of gene reactivation by CpG demethylation [35].

Analytical, diagnostic and therapeutic context of Decitabine

• Depression of DNA synthesis in mouse spleen after treatment with 5-aza-2'-deoxycytidine [21].
• In a renal cell culture line, treatment with 5-aza-2'-deoxycytidine resulted in reexpression of the VHL gene [36].
• The observation that 5-aza-2'-deoxycytidine-induced mutations are mediated by the enzyme suggests that novel inhibitors of DNA methyltransferase, which can inactivate the enzyme before its interaction with DNA, are needed for chemoprevention or long term therapy [18].
• The observation that nontoxic concentrations of the drug are able to induce the in vitro differentiation of both monoblastic and myeloblastic leukemic cells into mature elements may encourage the exploitation of the differentiating properties of 5-aza-2'-deoxycytidine in chemotherapy protocols for acute non-lymphoblastic leukemias [37].
• Decitabine was administered by intravenous infusion at a starting dose of 0.3 mg/kg per day, 5 days a week for 2 weeks, followed by a 4-week observation period [11].

References