Demethylating agent

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Demethylating agents are chemical substances that can inhibit methylation, resulting in the expression of the previously hypermethylated silenced genes (see Methylation#Cancer for more detail). Cytidine analogs such as 5-azacytidine (azacitidine) and 5-azadeoxycytidine (decitabine) are the most commonly used demethylating agents. They work by inhibiting DNA methyltransferases.[1] Both compounds have been approved in the treatment of myelodysplastic syndrome (MDS) by Food and Drug Administration (FDA) in United States. Azacitidine and decitabine are marketed as Vidaza and Dacogen respectively. Azacitidine is the first drug to be approved by FDA for treating MDS and has been given orphan drug status.[2][3] Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells.[4]

Mechanism of Action[]

There is very little known about the mechanism of action of these drugs. However, it was shown in 2015 that a possible mechanism of action of these drugs in colorectal cancer-initiating cells is through activating dsRNA expression which leads to the activation of the MDA5/MAVS RNA recognition pathway inducing some sort of viral mimicry inside the cell.[5]

Clinical Applications[]

The silencing of genes created by abnormal DNA methylation is a major contributor to the formation of cancerous tumors. Variations in DNA methylation of normal cells compared to malignant cells shows a prominent mechanism in how cancerous cells proliferate. Those variations are particularly prevalent in cell cycle regulation, DNA repair, and natural tumor suppression mechanisms.[6] A leading therapeutic strategy in treating solid tumors stems from the use of demethylating agents to suppress DNA methylation in cancerous growths. Azacitidine and decitabine are both frequently used demethylating agents while decitabine is significantly more potent in its demethylating abilities. Both of these drugs are inhibitors of DNA Methyltransferases (DNMT) which are enzymes that are responsible for methylating DNA. In the 1970’s, these drugs have shown promising results in hematological cancers in organisms such as mice. The FDA initially rejected the use of azacitidine clinically due to negative side effects caused by elevated toxicity levels. In later clinical trials performed on patients with MDS, myelodysplastic syndromes, azacitidine provided effective and exhibited consistent results which led to FDA approval in 2004. The commercial name of azacitidine became Vidaza. Decitabine, with the commercial name Dacogen, followed with FDA approval in 2006.[7] As more research is completed in the field of genetic mutations, specifically involving DNA Methylation, these drugs can be utilized to their maximum efficiency to clinically treat cancerous tumors. As of 2017, there were no approved demethylating agents for the treatment of solid tumors which can be a focus of research in the future. Treatment utilizing demethylating agents can have further clinical use by targeting cancer stem cells and triggering apoptosis.[8]

References[]

  1. ^ Holliday, R.; Ho, T. (2002). "DNA methylation and epigenetic inheritance". Methods. 27 (2): 179–83. doi:10.1016/S1046-2023(02)00072-5. PMID 12095278.
  2. ^ Issa, J. P., Kantarjian, H. M. and Kirkpatrick, P. (2005). "Azacitidine". Nat Rev Drug Discov. 4 (4): 275–6. doi:10.1038/nrd1698. PMID 15861567.CS1 maint: multiple names: authors list (link)
  3. ^ Gore, S. D., Jones, C. and Kirkpatrick, P. (2006). "Decitabine". Nat Rev Drug Discov. 5 (11): 891–2. doi:10.1038/nrd2180. PMID 17117522.CS1 maint: multiple names: authors list (link)
  4. ^ Villar-Garea A, Fraga MF, Espada J, Esteller M (2003). "Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells" (PDF). Cancer Research. 63 (16): 4984–9. PMID 12941824.
  5. ^ Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY; et al. (2015). "DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts". Cell. 162 (5): 961–73. doi:10.1016/j.cell.2015.07.056. PMC 4843502. PMID 26317465.CS1 maint: multiple names: authors list (link)
  6. ^ Navada, Shyamala C.; Steinmann, Juliane; Lübbert, Michael; Silverman, Lewis R. (2014-01-02). "Clinical development of demethylating agents in hematology". The Journal of Clinical Investigation. 124 (1): 40–46. doi:10.1172/JCI69739. ISSN 0021-9738. PMC 3871232. PMID 24382388.
  7. ^ Howell, Paul M.; Liu, Zixing; Khong, Hung T. (July 2010). "Demethylating Agents in the Treatment of Cancer". Pharmaceuticals. 3 (7): 2022–2044. doi:10.3390/ph3072022. PMC 4036667. PMID 27713340.
  8. ^ Linnekamp, J. F.; Butter, R.; Spijker, R.; Medema, J. P.; Laarhoven, H. W. M. van (2017-03-01). "Clinical and biological effects of demethylating agents on solid tumours – A systematic review". Cancer Treatment Reviews. 54: 10–23. doi:10.1016/j.ctrv.2017.01.004. ISSN 0305-7372. PMID 28189913.


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