5‐AZA‐2′‐deoxycytidine (5‐AZA‐CdR): a demethylating agent affecting development and reproductive capacity

Cisneros, Francisco Javier Barbancho; Branch, Stacy

doi:10.1002/jat.898

Cited by 12 publications

(10 citation statements)

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“…The DNA methylation inhibitor 5-aza-2′-deoxycytidine (5AzadC) interferes with testicular development (Cisneros and Branch, 2003; Choi et al, 2013). Since associated changes in testicular androgen synthesis would confound our study, we used an in vitro approach that recapitulates many features of in vivo prostate development (Doles et al, 2005) but isolates the UGS from influences of testes and other tissues.…”

Section: Resultsmentioning

confidence: 99%

DNA methylation of E-cadherin is a priming mechanism for prostate development

Keil

Abler

Mehta

et al. 2014

Developmental Biology

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In prostate and other epithelial cancers, E-cadherin (CDH1) is downregulated inappropriately by DNA methylation to promote an invasive phenotype. Though cancer frequently involves a reawakening of developmental signaling pathways, whether DNA methylation of Cdh1 occurs during organogenesis has not been determined. Here we show that DNA methylation of Cdh1 mediates outgrowth of developing prostate ducts. During the three-day gestational window leading up to and including prostate ductal initiation, Cdh1 promoter methylation increases and its mRNA and protein abundance decreases in epithelium giving rise to prostatic buds. DNA methylation is required for prostate specification, ductal outgrowth, and branching morphogenesis. All three endpoints are impaired by a DNA methylation inhibitor, which also decreases Cdh1 promoter methylation and increases Cdh1 mRNA and protein abundance. A CDH1 function-blocking antibody restores prostatic identity, bud outgrowth, and potentiates epithelial differentiation in the presence of the DNA methylation inhibitor. This is the first study to mechanistically link acquired changes in DNA methylation to the normal process of prostate organogenesis. We propose a novel mechanism whereby Cdh1 promoter methylation restricts Cdh1 abundance in developing prostate epithelium to create a permissive environment for prostatic bud outgrowth. Thus, DNA methylation primes the prostate primordium to respond to developmental cues mediating outgrowth, differentiation and maturation of the ductal network.

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Section: Resultsmentioning

confidence: 99%

DNA methylation of E-cadherin is a priming mechanism for prostate development

Keil

Abler

Mehta

et al. 2014

Developmental Biology

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“…Decitabine administration to neonatal/juvenile rats showed a general toxicity profile similar to that seen in adult rats [33][34][35]. Neurobehavioral development and reproductive The Oncologist ® 693 capacity were unaffected when neonatal/juvenile rats were treated at dose levels inducing myelosuppression.…”

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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“…5-Aza-CdR induces cell cycle arrest, cell differentiation, and cell death mainly by inhibiting post-replication methylation of DNA. In mice, exposure to 5-aza-CdR during development alters gene expression, causes malformations, and suppresses growth; administration of 5-aza-CdR to pregnant mice or rats at mid- or late-gestational periods elicits multiple characteristic defects [2]–[4].…”

Section: Introductionmentioning

confidence: 99%

5-Aza-2′-deoxycytidine Leads to Reduced Embryo Implantation and Reduced Expression of DNA Methyltransferases and Essential Endometrial Genes

et al. 2012

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BackgroundThe DNA demethylating agent 5-aza-2′-deoxycytidine (5-aza-CdR) incorporates into DNA and decreases DNA methylation, sparking interest in its use as a potential therapeutic agent. We aimed to determine the effects of maternal 5-aza-CdR treatment on embryo implantation in the mouse and to evaluate whether these effects are associated with decreased levels of DNA methyltransferases (Dnmts) and three genes (estrogen receptor α [Esr1], progesterone receptor [Pgr], and homeobox A10 [Hoxa10]) that are vital for control of endometrial changes during implantation.Methods and Principal FindingsMice treated with 5-aza-CdR had a dose-dependent decrease in number of implantation sites, with defected endometrial decidualization and stromal cell proliferation. Western blot analysis on pseudo-pregnant day 3 (PD3) showed that 0.1 mg/kg 5-aza-CdR significantly repressed Dnmt3a protein level, and 0.5 mg/kg 5-aza-CdR significantly repressed Dnmt1, Dnmt3a, and Dnmt3b protein levels in the endometrium. On PD5, mice showed significantly decreased Dnmt3a protein level with 0.1 mg/kg 5-aza-CdR, and significantly decreased Dnmt1 and Dnmt3a with 0.5 mg/kg 5-aza-CdR. Immunohistochemical staining showed that 5-aza-CdR repressed DNMT expression in a cell type–specific fashion within the uterus, including decreased expression of Dnmt1 in luminal and/or glandular epithelium and of Dnmt3a and Dnmt3b in stroma. Furthermore, the 5′ flanking regions of the Esr1, Pgr, and Hoxa10 were hypomethylated on PD5. Interestingly, the higher (0.5 mg/kg) dose of 5-aza-CdR decreased protein expression of Esr1, Pgr, and Hoxa10 in the endometrium on PD5 in both methylation-dependent and methylation-independent manners.ConclusionsThe effects of 5-aza-CdR on embryo implantation in mice were associated with altered expression of endometrial Dnmts and genes controlling endometrial changes, suggesting that altered gene methylation, and not cytotoxicity alone, contributes to implantation defects induced by 5-aza-CdR.

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5‐AZA‐2′‐deoxycytidine (5‐AZA‐CdR): a demethylating agent affecting development and reproductive capacity

Cited by 12 publications

References 54 publications

DNA methylation of E-cadherin is a priming mechanism for prostate development

DNA methylation of E-cadherin is a priming mechanism for prostate development

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

5-Aza-2′-deoxycytidine Leads to Reduced Embryo Implantation and Reduced Expression of DNA Methyltransferases and Essential Endometrial Genes

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