biostudies-literatureTsai HCNCI NIH HHS430-46https://www.ebi.ac.uk/biostudies/studies/S-EPMC3312044biostudies-literatureUnknown21(3)Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor "memory" response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes Cancer cellTransient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells.PMC3312044R01 CA043318CA 116160R01 CA116160R01 CA150142CA058184Yen RWVan Neste LMinn IWelm ALMatsui WPappou EShin JJBeaty RZahnow CAHarbom KMBrock MVJang YYSharkis SJLi HIssa JPRassool FVLin YCFeller-Kopman DRobert CBaylin SBCai YTsai HCHarris JAhuja NStearns VYarmus LBfalseTransient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells.Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor "memory" response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes 2012-01-01T00:00:00Z2012 Mar2026-05-03T18:50:10.438Z2026-04-07T19:32:55.766ZS-EPMC33120442243993810.1016/j.ccr.2011.12.029