title: DNA demethylation and invasive cancer: implications for therapeutics.
abstract: One of the hallmarks of cancer is aberrant DNA methylation, which is associated with abnormal gene expression. Both hypermethylation and silencing of tumour suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. As DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumour suppressor genes. Two cytosine analogues, 5-azacytidine (Vidaza) and 5-aza-2'-deoxycytidine, were approved by the Food and Drug Administration as antitumour agents in 2004 and 2006 respectively. However, these agents might cause activation of a panel of prometastatic genes in addition to activating tumour suppressor genes, which might lead to increased metastasis. This poses the challenge of how to target tumour suppressor genes and block cancer growth with DNA-demethylating drugs while avoiding the activation of prometastatic genes and precluding the morbidity of cancer metastasis. This paper reviews current progress in using DNA methylation inhibitors in cancer therapy and the potential promise and challenges ahead.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University Medical School, Montreal, QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Cheishvili
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University Medical School, Montreal, QC, Canada.|Department of Physiology Medical Sciences, University of Toronto 1 King's College Circle Toronto, ON, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Boureau
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University Medical School, Montreal, QC, Canada.|Sackler Program for Epigenetics and Developmental Psychobiology, McGill University Medical School, Montreal, QC, Canada.|Canadian Institute for Advanced Research, Faculty of Medicine, University of Toronto 1 King's College Circle Toronto, ON, Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D000077209:Decitabine; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine