The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1-0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1-2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.

中文翻译：

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地西他滨的非细胞毒性DNMT1靶向方案治疗髓样恶性肿瘤的丰富经验。

核苷类似物地西他滨可以消耗表观遗传调节剂DNA甲基转移酶1（DNMT1），这种作用在低浓度/剂量时会发生并饱和。追求这种分子靶向效应而不是高浓度/剂量产生的DNA损伤/细胞毒性的原因是，无细胞毒性的DNMT1耗竭甚至可以减少p53-null髓样恶性肿瘤的细胞，同时又不影响正常的造血作用。因此，我们确定了最低剂量的地西他滨（0·1-0·2 mg / kg），其在无脱靶的抗代谢作用/细胞毒性的情况下消耗了DNMT1，然后频繁地以每周1-2X的剂量给予这些耐受良好的剂量以增加S阶段依赖的DNMT1耗竭，并使用髓样恶性肿瘤注册表评估了以这种方式治疗的69例患者的长期预后。符合科学原理，