Therapeutic Applications of DNMT Inhibitors

Mithramydn A binds to GC-rich or CG-rich DNA sequences and blocks DNMT methylation activity. Docking of mithramycin A into the DNMTl catalytic domain indicates that the trisaccharide of the inhibitor can fit into the putative cytosine pocket and the aglycon core is bound betv een the two arms that fasten the hemimethylated DNA. 

Novel approaches to therapeutically downregulate DNA methylation include the DNMTl antisense compound MG98. However, clinical phase trials with the single drug showed no effect (partial or complete remission) or the effects could not be linked to DNMT inhibition [95-97]. 

The inhibitors available for human use, azacitidine and decitabine, have been approved for the treatment of myelodysplastic syndrome (MDS) [98, 99[. MDS summarizes a set of different conditions that affect the maturation of blood cells. It is a group of bone marrow stem cell malignancies that have a pathogenetic overlap with acute myeloid leukemia, show peripheral blood cytopenias and, in more advanced subtypes, varied degrees of maturation arrest [100]. Both drugs are approved for all subtypes of MDS. Response rates are usually around 30%. The question whether the clinical benefit results more from epigenetic effects and re-activation of silenced maturation factors or more from cytotoxic effects on the immature hyperproliferative cells remains open. 

Several studies have shown the ability of DNMT inhibitors to prevent cancer using different pathways [101-104]. Genistein demonstrated cancer chemopreventive activities in animal models [105]. It has been studied in different cancer cell lines and inhibition of cancer cell growth has been shown [106]. But several mechanisms, such as antihormonal effects, are discussed to explain this activity and the exact contribution of DNMT inhibition to in-vivo activity in cancer chemoprevention remains to be determined. 

We thank Frank Lyko, DKFZ Fleidelberg, for critical reading of the manuscript and Victor Marquez, NCI, for valuable discussion. 

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