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首页> 外文期刊>Cancer Cell >Transient Low Doses of DNA-Demethylating Agents Exert Durable Antitumor Effects on Hematological and Epithelial Tumor Cells
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Transient Low Doses of DNA-Demethylating Agents Exert Durable Antitumor Effects on Hematological and Epithelial Tumor Cells

机译：瞬时低剂量的DNA-脱甲基剂对血液和上皮肿瘤细胞具有持久的抗肿瘤作用

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摘要

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.
机译：启动子DNA高度甲基化和相关基因沉默的逆转是一种有吸引力的癌症治疗方法。 DNA甲基化抑制剂地西他滨和阿扎胞苷以较低，毒性较小的剂量有效治疗血液肿瘤。实验上，高剂量会引起快速的DNA损伤和细胞毒性，这不能解释患者观察到的反应时间延长。我们表明，培养和原发性白血病和上皮肿瘤细胞对临床相关的纳摩尔剂量的瞬时暴露，而不会引起立即的细胞毒性，产生抗肿瘤的“记忆”反应，包括抑制癌症干细胞样亚群。这些影响伴随着全基因组启动子DNA甲基化，基因重新表达和关键细胞调节途径中抗肿瘤变化的持续下降。小剂量地西他滨和阿扎胞苷可能在癌症治疗中具有广泛的适用性。

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