Author/Authors :
Tsai، نويسنده , , Hsing-Chen and Li، نويسنده , , Huili and Van Neste، نويسنده , , Leander and Cai، نويسنده , , Weitao Yi and Robert Goldberg، نويسنده , , Carine and Rassool، نويسنده , , Feyruz V. and Shin، نويسنده , , James J. and Harbom، نويسنده , , Kirsten M. and Beaty، نويسنده , , Robert and Pappou، نويسنده , , Emmanouil and Harris، نويسنده , , James H. Yen b، نويسنده , , Ray-Whay Chiu and Ahuja، نويسنده , , Nita and Brock، نويسنده , , Malcolm V. and Stearns، نويسنده , , Vered and Feller-Kopman، نويسنده , , David and Yarmus، نويسنده , , Lonny B. and Lin، نويسنده , , Yi-Chun and Welm، نويسنده , , Alana L. and Issa، نويسنده , , Jean-Pierre and Minn، نويسنده , , Il and Matsui، نويسنده , , William and Jang، نويسنده , , Yoon-Young and Sharkis، نويسنده , , Saul J. and Baylin، نويسنده , , Stephen B. and Zahnow، نويسنده , , Cynthia A.، نويسنده ,
Abstract :
Summary
al 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.
