Modulators of DNA methylation and histone acetylation

The distribution of epigenetic alterations, such as DNA methylation and histone modifications, is abnormal in cancer cells, and drugs that influence these changes are currently being used effectively in the treatment of hematopoietic malignancies. Two hypomethylating agents, 5-azacytidine and decitabine, are FDA-approved for the treatment of myelodysplastic syndromes, and one histone deacetylase inhibitor, vorinostat, was recently FDA-approved for patients with refractory cutaneous T-cell lymphoma. Generally, these agents are very well tolerated, with myelosuppression being the major side effect. Although they are thought to work by re-organizing chromatin to allow expression of genes silenced by DNA hypermethylation and repressive histone modifications, the precise mechanism of action of these agents is not yet clear. Current studies are examining the utility of these agents for the treatment of solid tumors as well as testing these drugs in combination to treat a variety of malignancies.