Disease relevance of Azacitidine

• Further studies will be required to evaluate the efficacy, risks, and long-term toxicity of 5-azacytidine (or related compounds) before this approach can be used as a therapy for patients with disorders of hemoglobin synthesis [1].
• The increase in fetal-hemoglobin synthesis in patients with beta-thalassemia or sickle-cell anemia induced by 5-azacytidine has been attributed to hypomethylation of DNA in the region of the gamma-globin genes [2].
• Brief report: treatment with azacitidine of patients with end-stage beta-thalassemia [3].
• Activation by 5-azacytidine occurred only in differentiated teratocarcinoma cells [4].
• Derivation of macrophage-like lines from the pre-B lymphoma ABLS 8.1 using 5-azacytidine [5].

Psychiatry related information on Azacitidine

• Differential chromosome sensitivity to 5-azacytidine in Alzheimer's disease [6].

High impact information on Azacitidine

• Fourth, C3H10T1/2 cells expressing antisense E2A transcripts contain low levels of E2A gene products and display less terminal muscle differentiation when infected with retroviral MyoD or when challenged to differentiate with 5-azacytidine treatment [7].
• Treatment of the transfected cells with the DNA demethylating agent 5-azacytidine reactivates the thyroglobulin promoter and yields stable G418-resistant clones [8].
• 5-azacytidine treatment of mouse C3H10T1/2 embryonic fibroblasts converts them to myoblasts at a frequency suggesting alteration of one or only a few closely linked regulatory loci [9].
• Stable myoblast cell lines were isolated after a brief exposure of mouse fibroblasts (10T1/2 cells) to 5-azacytidine [10].
• Altering gene expression with 5-azacytidine [11].

Chemical compound and disease context of Azacitidine

• For a comparison of the kinetics of the cytotoxicity of dihydro-5-azacytidine hydrochloride (DHAzaCR) and 5-azacytidine (AzaCR) in L1210 leukemia, the spleen colony assay was used to determine the surviving fraction of normal hematopoietic colony-forming units (NCFU) and leukemia colony-forming units (LCFU) [12].
• Both immunogenic and nonimmunogenic variant clones were isolated from a recently obtained spontaneous murine adenocarcinoma after treatment (xenogenization) with either the mutagen ethyl methanesulfonate or the DNA hypomethylating agent, and "gene activator," 5-azacytidine [13].
• Adoptive transfer of 5-azacytidine- or procainamide-treated cells into unirradiated syngeneic recipients induced an immune complex glomerulonephritis and IgG anti-DNA and antihistone antibodies [14].
• Mutagenesis of mouse hepatitis virus with 5-azacytidine or 5-fluorouracil yielded several temperature-sensitive mutants [15].
• Bisulfite analysis of cells in which 5-azacytidine treatment induced GFP expression revealed measurable but incomplete demethylation of the provirus [16].

Biological context of Azacitidine

• Although 5-azacytidine decreased the level of DNA methylation, it did not activate M-MuLV in undifferentiated cells [4].
• The nucleoside analog 5-azacytidine (5-aza-CR) induced marked changes in the differentiated state of cultured mouse embryo cells and also inhibited the methylation of newly synthesized DNA [17].
• Five subclones of the 10T1/2 line which were the progeny of single cells all expressed both the muscle and fat phenotypes following 5-azacytidine treatment [18].
• 5-Azacytidine permits gene activation in a previously noninducible cell type [19].
• Conversion of 10T1/2 cells by 5-azacytidine provides a model for studying regulatory genes involved in cell lineage determination [20].

Anatomical context of Azacitidine

• 5-Azacytidine converts the mouse embryonic cell line C3H 10T1/2 into differentiated chondrocytes, adipocytes, and skeletal muscle [20].
• 5-Azacytidine induction of stable mesodermal stem cell lineages from 10T1/2 cells: evidence for regulatory genes controlling determination [20].
• We propose that 5-azacytidine converts 10T1/2 cells by hypomethylation of "determination" regulatory loci which establish lineages of stem cells with a restricted potential to differentiate into muscle, cartilage, or fat cells [20].
• Clonal and 2D protein gel analyses demonstrate that 5-azacytidine converts 10T1/2 cells into three stably determined, but undifferentiated, stem cell lineages which can differentiate into myofibers, chondrocytes, and adipocytes [20].
• However, if HeLa cells were treated with 5-azacytidine (5-aza-CR) prior to fusion, muscle gene expression was induced in the heterokaryons [19].

Associations of Azacitidine with other chemical compounds

• Three new mesenchymal phenotypes were expressed in cultures of Swiss 3T3 and C3H/10T1/2CL8 mouse cells treated with 5-azacytidine or 5-aza-2'-deoxycytidine [18].
• When W7 cells are treated for a few hours with 5-azacytidine, the MT-I gene becomes inducible by both cadmium and glucocorticoids [21].
• Addition of hydroxyurea along with 5-azacytidine prevents MT-I gene induction, suggesting that incorporation of 5-azacytidine into DNA is required before this gene can be activated [21].
• Transient exposure of cells to 5-azacytidine, a cytosine analogue which cannot be methylated at the 5 position, results in the hypomethylation and transcriptional activation of ev-1, as well as the acquisition of at least one nuclease-hypersensitive site within the chromosomal domain of ev-1 [22].
• It is known that treatment of cells with 5-azacytidine can induce transcriptional activation of "silent" genes through a reduction of DNA 5-methylcytosine content, a process that can also be effected by mutagenic DNA alkylating agents such as EMS and MNNG [23].

Gene context of Azacitidine

• The studies show that 5-azacytidine can induce heritable changes in the inactive human X chromosome resulting in the expression of G6PD activity at a level lower than that from an active human X chromosome [24].
• SLC5A8 exon 1 methylated cells were uniformly silenced for SLC5A8 expression, but reactivated expression on treatment with a demethylating drug, 5-azacytidine [25].
• In addition, our observations of continued XIST expression in 5aC-treated hybrids with reactivated genes indicates that such expression is not sufficient for the maintenance of X inactivation [26].
• Megakaryocytic differentiation induced in 416B myeloid cells by GATA-2 and GATA-3 transgenes or 5-azacytidine is tightly coupled to GATA-1 expression [27].
• Furthermore, 416B cells treated with the DNA demethylating agent 5-azacytidine underwent megakaryocytic differentiation accompanied by a marked increase in the level of GATA-1 mRNA but not that of GATA-2 or GATA-3 [27].

Analytical, diagnostic and therapeutic context of Azacitidine

• TgTF1 cannot be detected in transformed cells but reappears after treatment with 5-azacytidine at 39 degrees C. Restoration of Ras activity at 33 degrees C leads to the rapid loss of TgTF1 and G418 resistance [8].
• Results of chemotherapy with doxorubicin and 5-azacytidine yielded a somewhat better survival rate than a combined program with doxorubicin and radiotherapy [28].
• Two demethylating drugs, 5-azacytidine and 5-aza-deoxycytidine, are currently being tested in clinical trials, and several others are in preclinical development [29].
• METHODS AND RESULTS: In vitro studies: BMCs from adult rats were cultured in cell culture medium (control) and medium with 5-azacytidine (5-aza, 10 micromol/L), TGFbeta1 (10 ng/mL), or insulin (1 nmol/L) (n=6, each group) [30].
• Western blotting for hMLH1 was performed on methylated cell lines before and after the addition of the demethylating agent 5-azacytidine [31].

References