期刊
CANCER CELL
卷 21, 期 3, 页码 430-446出版社
CELL PRESS
DOI: 10.1016/j.ccr.2011.12.029
关键词
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资金
- National Institutes of Health [CA 116160]
- Lung Spore in Cancer NCI [CA058184]
- Entertainment Industry Foundation
- Lee Jeans
- Samuel Waxman Cancer Research Foundation
- Irving A. Hansen Memorial Foundation
- Safeway Foundation
- Department of Defense [BC075015]
- Huntsman Cancer Foundation
- Cindy Rosencrans Fund for Triple Negative Breast Cancer Research.
- SU2C
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 in key cellular regulatory pathways. Low-dose decitabine and azacitidine may have broad applicability for cancer management.
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