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Reactivation of epigenetically silenced genes by DNA methyltransferase inhibitors: basic concepts and clinical applications Mund C; Brueckner B; Lyko FEpigenetics 2006[Jan]; 1 (1): 7-13Hypermethylation of tumor suppressor genes is one of the most consistent hallmarks of human cancers. This epigenetic alteration has been associated with gene silencing and thus represents an important pathway for generating loss-of-function mutations. In this review, we survey the available literature on systematic, genome-wide approaches aimed at the identification of epigenetically silenced loci. These studies uncovered a variety of diverse genes, but a common signature for epigenetic reactivation has not been identified. Nevertheless, DNA methyltransferase inhibitors have shown significant clinical benefits, mostly in the therapy of leukemias. Recent analyses revealed substantial drug-induced methylation changes that can now be used as endpoints for the further refinement of clinical treatment schedules. Further optimization of epigenetic cancer therapies should be feasible through the use of novel DNA methyltransferase inhibitors with improved specificity. Rational design of epigenetic inhibitors might provide the foundation for a broader use of these drugs in the treatment of cancer.|Animals[MESH]|DNA Methylation/drug effects[MESH]|DNA Modification Methylases/*antagonists & inhibitors[MESH]|Enzyme Inhibitors/chemistry/pharmacology/*therapeutic use[MESH]|Epigenesis, Genetic/*drug effects[MESH]|Gene Silencing/drug effects[MESH]|Humans[MESH] |
