Development of DNA methyltransferase inhibitors for the treatment of neoplastic diseases.
Although chemotherapy is considered the mainstay of cancer therapy, unfortunate side effects of chemotherapy create a continuous demand for developing other novel and specific targets for cancer therapy. Re-expression of epigenetically silenced tumor suppressor genes is a rational strategy for the treatment of human neoplasms. Epigenetic modifiers like DNA methyltransferase (DNMT) inhibitors and histone deacteylase (HDAC) inhibitors induce the re-expression of epigenetically silenced genes in vitro and in vivo. Moreover, they demonstrate safety and efficacy against neoplastic diseases in clinical trials. DNMT inhibitors like 5-azacytidine and 5-aza-2'-deoxycytidine are currently FDA approved for the treatment of myelodysplastic syndrome. Nonetheless, the mechanism of action behind their clinical efficacy remains unclear. Ongoing clinical trials are attempting to identify tumor suppressor genes that upon re-expression can induce remission and cure in patients. On the other hand, the pleiotropic biological effects of DNMT inhibitors and recent reports demonstrating lack of association between clinical response and methylation reversal of candidate tumor suppressor genes, suggest a complex mechanism behind their clinical efficacy that may involve a cytotoxic effect.
Fandy
Tamer E
TE
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA. tfandy@jhu.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D044127:Epigenesis, Genetic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D006655:Histone Deacetylases