Demethylation of DNA by decitabine in cancer chemotherapy.
Genes involved in all aspects of tumor development and growth can become aberrantly methylated in tumor cells, including genes involved in apoptosis and cell cycle regulation. Decitabine, 2'-deoxy-5-azacytidine, can inhibit DNA methyltransferases and reverse epigenetic silencing of aberrantly methylated genes. Nucleoside DNA methyltransferase inhibitors, such as decitabine, have been reported to have antitumor activity, especially against hematologic malignancies. Such demethylating agents have been proposed to reactivate tumor suppressor genes aberrantly methylated in tumor cells, leading to inhibition of tumor growth. An important consequence of this is that, unlike conventional cytotoxic agents, it may be best to use such drugs at concentrations lower than the maximum tolerated dose and in a manner dependent on their demethylating activity. Furthermore, synergistic activity with other types of investigational epigenetic therapies and existing chemotherapies opens the possibility of rational combinations and scheduling of these agents based on their biologic activity.
Brown
Robert
R
Cancer Research UK Beatson Laboratories, Centre for Oncology and Applied Pharmacology, Glasgow University, Glasgow G61 1BD, UK. R.Brown@Beatson.gla.ac.uk
Plumb
Jane A
JA
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019175:DNA Methylation; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine