Issa Jean-Pierre
Section of Translational Research, Department of Leukemia at the MD Anderson Cancer Center, University of Texas, Houston 77030, USA.
Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S24-9. doi: 10.1038/ncponc0355.
Azacitidine (Vidaza, Pharmion Corp., Boulder, CO, USA) and decitabine (Dacogentrade mark, SuperGen, Inc., Dublin, CA, USA, and MGI Pharma, Inc., Bloomington, MN, USA) are DNA methyltransferase (DNMT) inhibitors that have clinical activity in patients with myelodysplastic syndromes. Mechanism-based laboratory studies suggest that clinical optimization of therapy with DNMT inhibitors needs to include optimizing intracellular drug uptake and maximizing drug exposure over time while still using lower doses to avoid cytotoxicity. Clinical studies suggest that increased dose intensity and multiple cycles of administration substantially increase response rates. Other strategies for optimizing the efficacy of DNMT inhibitor therapy also include identification of patients that are best qualified for treatment, and defining in vivo mechanisms of patient responses. In the future, combination strategies to increase gene reactivation and to take advantage of increased expression of target genes may be critical for achieving optimal results.
阿扎胞苷（维达莎，美国科罗拉多州博尔德市Pharmion公司）和地西他滨（达珂，美国加利福尼亚州都柏林市SuperGen公司以及美国明尼苏达州布卢明顿市MGI制药公司的商标）是DNA甲基转移酶（DNMT）抑制剂，对骨髓增生异常综合征患者具有临床活性。基于机制的实验室研究表明，DNMT抑制剂治疗的临床优化需要包括优化细胞内药物摄取以及随着时间推移使药物暴露最大化，同时仍使用较低剂量以避免细胞毒性。临床研究表明，增加剂量强度和多个给药周期可大幅提高缓解率。优化DNMT抑制剂治疗疗效的其他策略还包括识别最适合治疗的患者，以及确定患者反应的体内机制。未来，增加基因重新激活并利用靶基因表达增加的联合策略对于取得最佳效果可能至关重要。
