Our understanding of how to use DNA methyltransferase (DNMT) inhibitors to target DNA methylation in cancer therapy have come a long way since the nucleotide analogs 5-Azacytidine (5-Aza-CR, Vidaza) and 5-Aza-2’-deoxycytidine (5-Aza-2-CdR, Decitabine) were approved by the FDA over a decade ago for the treatment of myeloid dysplastic syndrome. First developed as chemotherapeutic agents, these compounds (hereon referred collectively as AZA) were found to reduce DNA methylation level in tumor cells, thus acting as demethylating agents. DNA methylation is a covalent addition of a methyl group at the fifth carbon of cytosines that are present in the context of CpG dinucleotides. DNA methylation is a component of epigenetic machineries, which in normal cells, is critical for silencing of retrotransposons, and during genomic silencing and X-inactivation. Although the levels may vary, global changes in DNA methylation have been shown to be a key feature of cancer cells. Furthermore, DNA methylation is dynamic and pharmacologically reversible and thus, an attractive target for cancer therapy.
Decades of study have shown that while cancer cells exhibit global decrease in DNA methylation, there are punctate regions throughout the genome that have markedly increased DNA methylation level. This hypermethylation pattern is strongly associated with the silencing of genes, including tumor suppressor genes, leading to gene expression profile that favor uncontrollable cell growth. 
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