Plimack Elizabeth R, Kantarjian Hagop M, Issa Jean-Pierre
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Leuk Lymphoma. 2007 Aug;48(8):1472-81. doi: 10.1080/10428190701471981.
DNA methylation is responsible for abnormal silencing of many genes, including tumor suppressor genes, in cancer. Decitabine, an S-phase specific inhibitor of DNA methyltransferase, has been shown to decrease levels of abnormal methylation in neoplasia. Though initially investigated at high doses as a cytotoxic agent, recent studies show that when administered at low doses, the hypomethylating activity of decitabine is increased with a demonstrated increase in activity in hematopoietic malignancies. Multiple clinical trials, both in the United States and in Europe, have demonstrated the efficacy of decitabine in acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome (MDS). Recently approved by the United States Food and Drug Administration for the treatment of (MDS), decitabine represents an effective and well-tolerated therapeutic option in this disease, for which treatment options were previously scarce. While the activity in MDS is promising, primary and secondary resistance remain a problem. Investigations of combinations of decitabine with other agents, including histone deacetylase inhibitors, are currently ongoing in the hope of substantially prolonging survival in patients with hematologic malignancies.
DNA甲基化是导致癌症中包括肿瘤抑制基因在内的许多基因异常沉默的原因。地西他滨是一种DNA甲基转移酶的S期特异性抑制剂，已被证明可降低肿瘤形成过程中异常甲基化的水平。尽管最初作为一种细胞毒性药物进行高剂量研究，但最近的研究表明，低剂量给药时，地西他滨的去甲基化活性会增强，在血液系统恶性肿瘤中其活性已得到证实。美国和欧洲的多项临床试验已证明地西他滨在急性髓系白血病、慢性髓系白血病和骨髓增生异常综合征（MDS）中的疗效。最近，地西他滨被美国食品药品监督管理局批准用于治疗MDS，它是这种疾病一种有效且耐受性良好的治疗选择，而此前针对该疾病的治疗选择很少。虽然地西他滨在MDS中的活性很有前景，但原发性和继发性耐药仍然是一个问题。目前正在研究地西他滨与其他药物（包括组蛋白去乙酰化酶抑制剂）的联合使用，以期大幅延长血液系统恶性肿瘤患者的生存期。
