Cancer Biology Graduate Program.
Medical Scientist Training Program.
JCI Insight. 2022 Nov 22;7(22):e159419. doi: 10.1172/jci.insight.159419.
The DNA methyltransferase inhibitor decitabine has classically been used to reactivate silenced genes and as a pretreatment for anticancer therapies. In a variation of this idea, this study explores the concept of adding low-dose decitabine (DAC) following administration of chemotherapy to bolster therapeutic efficacy. We find that addition of DAC following treatment with the chemotherapy agent gemcitabine improves survival and slows tumor growth in a mouse model of high-grade sarcoma. Unlike prior studies in epithelial tumor models, DAC did not induce a robust antitumor T cell response in sarcoma. Furthermore, DAC synergizes with gemcitabine independently of the immune system. Mechanistic analyses demonstrate that the combination therapy induces biphasic cell cycle arrest and apoptosis. Therapeutic efficacy was sequence dependent, with gemcitabine priming cells for treatment with DAC through inhibition of ribonucleotide reductase. This study identifies an apparently unique application of DAC to augment the cytotoxic effects of conventional chemotherapy in an immune-independent manner. The concepts explored in this study represent a promising paradigm for cancer treatment by augmenting chemotherapy through addition of DAC to increase tolerability and improve patient response. These findings have widespread implications for the treatment of sarcomas and other aggressive malignancies.
DNA 甲基转移酶抑制剂地西他滨经典地被用于重新激活沉默基因，并作为抗癌治疗的预处理。在这一理念的变体中，本研究探索了在化疗后添加低剂量地西他滨（DAC）以增强治疗效果的概念。我们发现，在用化疗药物吉西他滨治疗后添加 DAC 可以提高高级肉瘤小鼠模型的存活率并减缓肿瘤生长。与上皮肿瘤模型中的先前研究不同，DAC 没有在肉瘤中诱导出强烈的抗肿瘤 T 细胞反应。此外，DAC 与吉西他滨协同作用独立于免疫系统。机制分析表明，联合治疗诱导双相细胞周期停滞和细胞凋亡。治疗效果具有序列依赖性，通过抑制核糖核苷酸还原酶，吉西他滨使细胞对 DAC 治疗产生耐药性。本研究确定了 DAC 的一种明显独特的应用，即通过添加 DAC 增强常规化疗的细胞毒性作用，从而以免疫独立的方式提高耐受性并改善患者反应。这些发现对通过添加 DAC 增强化疗以提高耐受性和改善患者反应来治疗肉瘤和其他侵袭性恶性肿瘤具有广泛的意义。
