Baylor College of Medicine & Michael E DeBakey VA Medical Center, Houston, TX 77030, USA.
Future Oncol. 2011 Mar;7(3):447-63. doi: 10.2217/fon.11.9.
Silencing of tumor suppressor genes by promoter-region methylation as an epigenetic mechanism of gene regulation is increasingly recognized as beneficial in cancer. Initially developed as cytotoxic high-dose therapies, azacitidine and decitabine are now being reinvestigated in lower-dose cancer treatment regimens with a different paradigm - hypomethylation. Recent evidence for benefit in myelodysplastic syndromes and acute myeloid leukemias has renewed interest in hypomethylation as a therapeutic option in epithelial cancers. In this article, we describe the mechanistic aspects of DNA methylation, which alters gene expression, and review the evidence for hypomethylation as a therapeutic option in urologic cancers. Potential correlative studies that may assist in developing tailored therapy with hypomethylating agents are reviewed. Given that the population with urologic cancers is typically elderly with multiple comorbidities, the excellent tolerability of lower-dose hypomethylating agents provides a high therapeutic index and rational development is warranted, bearing in mind that the cytostatic and delayed activity present challenges in the choice of appropriate trial end points.
肿瘤抑制基因启动子区域甲基化沉默作为一种表观遗传基因调控机制，在癌症中越来越被认为是有益的。阿扎胞苷和地西他滨最初被开发为细胞毒性高剂量疗法，现在正在以不同的范式——低剂量癌症治疗方案中重新研究，即低甲基化。在骨髓增生异常综合征和急性髓系白血病中的获益证据，重新激发了低甲基化作为上皮性癌症治疗选择的兴趣。在本文中，我们描述了改变基因表达的 DNA 甲基化的机制方面，并回顾了低甲基化作为泌尿科癌症治疗选择的证据。还回顾了可能有助于开发针对低甲基化药物的个体化治疗的潜在相关研究。鉴于患有泌尿科癌症的人群通常是患有多种合并症的老年人，低剂量低甲基化药物的良好耐受性提供了高治疗指数，因此合理开发是合理的，需要牢记的是，细胞毒性和延迟活性在选择适当的试验终点方面存在挑战。
