Chapter 39 - DNA Demethylation Agents in Clinical Medicine

Abstract

DNA methylation is a fundamental epigenetic mechanism that is involved in long-term programming of gene expression and in determining cell fate by regulating cell-specific gene expression profiles. Studies 3 decades ago revealed aberrant DNA methylation in cancer, which was confirmed by a vast body of literature and perfected by advancements in molecular biology and DNA methylation mapping methods including high-resolution genome wide mapping of tumor DNA methylation from different origins and stages. This has led to the suggestion that pharmacological interference aimed at reversing DNA methylation aberrations could lead to reversal of cancer. Although early studies revealed global hypomethylation in cancer, later discoveries highlighted the hypermethylation of tumor suppressor genes. This body of data in addition to the finding that DNA methyltransferases (DNMTs) are upregulated in many cancer led to the hypothesis that DNMT is an anticancer target. Recent discoveries in behavioral and neuroepigenetics identified new possible therapeutic targets for DNA methylation inhibition for treating mental health disease. Two “old nucleoside analogs” that were developed in the mid-20th century that were later shown to inhibit DNA methylation, 5-azacytidine (AZA) and 5-aza 2′ deoxycytidine (DAC) have been approved almost a decade ago for treatment of certain blood cancers and are still the only clinically tested DNA methylation inhibitors. These agents were shown to increase objective responses and overall survival in MDS and AML, however they are not “curative.” Different dosing and scheduling strategies are being tested as well as combinations, with other classical or new anticancer agents. Attempts to treat solid cancers, with DNA demethylation agents have been inconclusive as of yet. There are possible therapeutic opportunities for DNMT inhibitors in mental health as well. However, there is a dire need for developing new less toxic isoform-specific catalytic DNA methylation inhibitors that could cross the brain–blood barrier.