Abstract 995: Transient low doses of DNA demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells
| Autor: | Alana L. Welm, Yi Cai, Feyruz V. Rassool, Emmanouil P. Pappou, James C. Harris, Il Minn, Malcolm V. Brock, Vered Stearns, Stephen B. Baylin, Carine Robert, Jean Pierre J. Issa, Robert Beaty, Yoon-Young Jang, Yi Chun Lin, Hsing-Chen Tsai, Leander Van Neste, Ray-Whay Chiu Yen, Huili Li, William Matsui, David Feller-Kopman, Kirsten Harbom, Cynthia A. Zahnow, Nita Ahuja, James Shin, Saul J. Sharkis |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Cancer Research. 72:995-995 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitors, decitabine (5-aza-2′-deoxycytidine) and azacitidine (5-azacytidine) are proving efficacious clinically for hematological neoplasms, especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response often seen in patients. We now show that transient exposure of cultured and primary leukemic and epithelial tumor cells to decitabine or azacitidine at clinically-relevant nanomolar doses, without causing immediate cytotoxicity, produces a “memory” for anti-tumor responses, including potent inhibition of subpopulations of cancer, stem-like cells which often resist other therapies. These inhibitory effects are accompanied by sustained decreases in genome-wide promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, such as cell cycle events mediated through FOXM1, cell invasion and motility, and granulocyte and breast cancer cell maturation. Notably, most of the key pathways altered by decitabine or azacitidine involve high priority targets for pharmacologic anti-cancer strategies, which provides molecular basis for possible combination therapies. Thus, low dose decitabine and azacitidine regimens may potentially have broad applicability for cancer management. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 995. doi:1538-7445.AM2012-995 |
| Databáze: | OpenAIRE |
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