Saunthararajah Yogen
1Hematologic Malignancies and Blood Disorders, Cleveland Clinic, Cleveland, OH; and.
Hematology Am Soc Hematol Educ Program. 2013;2013:511-21. doi: 10.1182/asheducation-2013.1.511.
Clinical experience with 5-azacytidine and decitabine treatment of myelodysplastic syndromes (MDS), complemented by biological and pharmacological studies, has revealed compelling mechanism of action differences compared with traditional myeloid cancer treatment mainstays such as cytarabine. For example, 5-azacytidine and decitabine produce remissions and better overall survival in MDS with high-risk chromosome abnormalities at a surprisingly high rate, consistent with experimental observations that noncytotoxic DNA methyltransferase depletion by 5-azacytidine/decitabine can trigger cell cycle exit independently of p53, thus circumventing a basis for resistance to apoptosis-based DNA-damaging therapy. That responses cut across the chaotic genomic landscape of MDS highlights common threads in disease, such as high expression in myeloblasts of differentiation-driving transcription factors yet paradoxical epigenetic suppression of proliferation-terminating late-differentiation genes. Less toxic regimens (lower dosages but more frequent administration) of 5-azacytidine/decitabine have been more successful, underscoring the importance of preserving functionally normal stem cells, which are rendered more precious by attrition from age, previous cytotoxic treatments, and the disease process and are needed to relieve cytopenias, the cause of morbidity and mortality. Also emphasized is that there can be no therapeutic benefit, regardless of mutation or cytogenetic subtype, if DNA methyltransferase is not depleted by sufficient overlap between intracellular drug half-lives and S-phase entries of malignant cells. Improved understanding of mechanism-of-action differences demands new approaches, from historic (but not scientific) more-is-better and one-size-fits-all empiricism to pharmacodynamic-based designs and combinations directed not solely at suppressing malignant clones, but at improving therapeutic indices.
5-氮杂胞苷和地西他滨治疗骨髓增生异常综合征（MDS）的临床经验，辅以生物学和药理学研究，揭示了与传统髓系癌症治疗主要药物（如阿糖胞苷）相比令人信服的作用机制差异。例如，5-氮杂胞苷和地西他滨在伴有高危染色体异常的MDS中能产生缓解并显著提高总生存率，这与实验观察结果一致，即5-氮杂胞苷/地西他滨对DNA甲基转移酶的非细胞毒性消耗可独立于p53触发细胞周期退出，从而规避了基于凋亡的DNA损伤疗法的耐药基础。这些反应跨越了MDS混乱的基因组格局，突显了疾病中的共同线索，例如分化驱动转录因子在成髓细胞中高表达，但增殖终止的晚期分化基因却存在矛盾的表观遗传抑制。5-氮杂胞苷/地西他滨的低毒方案（较低剂量但给药更频繁）更为成功，这强调了保留功能正常干细胞的重要性，这些干细胞因年龄、先前的细胞毒性治疗和疾病进程而减少，变得更加珍贵，对于缓解血细胞减少症（发病和死亡的原因）是必需的。还强调的是，如果细胞内药物半衰期与恶性细胞S期进入之间没有足够的重叠以消耗DNA甲基转移酶，那么无论突变或细胞遗传学亚型如何，都不会有治疗益处。对作用机制差异的更好理解需要新的方法，从历史上（但不科学）的越多越好和一刀切的经验主义，转向基于药效学的设计和联合用药，不仅旨在抑制恶性克隆，还旨在提高治疗指数。
