Innovative approaches to the clinical development of DNA methylation inhibitors as epigenetic remodeling drugs.
The most extensively studied inhibitors of DNA methylation are the cytidine analogs 5-azacytidine (5-aza-CR; azacitidine) and 5-aza-2'- deoxycytidine (5-aza-CdR; decitabine). Despite decades of nonclinical and clinical research, there remains considerable interest in finding innovative and better ways to use these DNA methyltransferase (DNMT) inhibitors. A mounting body of data supports the role of methylation in silencing genes involved in tumor growth and resistance. This information has fueled further nonclinical and clinical research on ways to use inhibitors of methylation to restore normal gene expression and function. As such, recent clinical strategies have shifted from simply evaluating cytotoxic effects to exploring and optimizing the ability of these agents to restore or reactivate gene expression and putative targets. This article considers innovative approaches to develop and evaluate inhibitors of DNA methylation as epigenetic remodeling agents for the treatment of cancer. These include optimization of dose and schedule, restoration or enhancement of sensitivity to other treatment modalities, and combinations with other agents including histone deacetylase inhibitors.
Murgo
Anthony J
AJ
Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 6130 Executive Boulevard, Bethesda, MD 20852, USA. murgoa@mail.nih.gov
D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D002986:Clinical Trials as Topic; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D015254:DNA Modification Methylases; D001374:Azacitidine