Taylor S M
Department of Microbiology, University of Southern California, Los Angeles 90033.
Leukemia. 1993 May;7 Suppl 1:3-8.
5-Azacytidine (5-aza-CR) and 5-aza-2'-deoxycytidine (5-aza-CdR), analogs of cytidine modified in position 5, were originally developed as antitumor agents, and have been useful in the treatment of both childhood and adult leukemias. These agents are cytotoxic per se, but also induce differentiation in several experimental systems, most notably the induction of muscle, adipocytes, and chondrocytes in cultures of drug-treated mouse embryo fibroblasts. The mechanisms underlying this drug-induced differentiation have been difficult to unravel, a fact which limits the rational design of differentiation therapy as a modulator of cancer using these agents. Induction of new developmental pathways in cultured cells involves stable, heritable changes, presumably of an epigenetic nature. Our early studies demonstrated that changes in methylation of cytosine in DNA occurred concurrently with changes in developmental potential, and that the presence of 5-azacytosine in DNA interfered with the action of DNA methyltransferase. Since DNA methylation is believed to be involved at some level in the regulation of gene expression, the hypothesis was developed that changes in methylation allowed the expression of new genes whose activity initiated new pathways of differentiation. The characterization of this drug-induced system of differentiation has therefore opened the way to identifying genes directly involved in the initiation or modification of pathways of differentiation. The first of these was MyoD, a member of a family of myogenic determination genes. Expression of MyoD in myogenic cell lines has been correlated with loss of methylation at specific sites in the genome, but the critical events leading to expression of MyoD and muscle differentiation are poorly understood. Recent developments in understanding this mechanism are discussed.
5-氮杂胞苷（5-aza-CR）和5-氮杂-2'-脱氧胞苷（5-aza-CdR）是胞苷在5位修饰的类似物，最初被开发用作抗肿瘤药物，已用于治疗儿童和成人白血病。这些药物本身具有细胞毒性，但也能在多个实验系统中诱导分化，最显著的是在经药物处理的小鼠胚胎成纤维细胞培养物中诱导肌肉、脂肪细胞和软骨细胞的生成。这种药物诱导分化的潜在机制一直难以阐明，这一事实限制了将分化疗法合理设计为使用这些药物的癌症调节剂。在培养细胞中诱导新的发育途径涉及稳定的、可遗传的变化，推测是表观遗传性质的。我们早期的研究表明，DNA中胞嘧啶甲基化的变化与发育潜能的变化同时发生，并且DNA中5-氮杂胞嘧啶的存在会干扰DNA甲基转移酶的作用。由于人们认为DNA甲基化在某种程度上参与基因表达的调控，因此提出了这样的假设：甲基化的变化允许新基因表达，其活性启动了新的分化途径。因此，这种药物诱导的分化系统的特征为鉴定直接参与分化途径启动或修饰的基因开辟了道路。其中第一个是MyoD，它是肌源性决定基因家族的一员。MyoD在肌源性细胞系中的表达与基因组中特定位点甲基化的丧失相关，但导致MyoD表达和肌肉分化的关键事件仍知之甚少。本文讨论了在理解这一机制方面的最新进展。
