Cheson B D, Zwiebel J A, Dancey J, Murgo A
Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.
Semin Oncol. 2000 Oct;27(5):560-77.
Few chemotherapy agents have demonstrated activity in patients with myelodysplastic syndromes (MDS) and supportive management remains the standard of care. An increasing number of new drugs in development are being directed at specific molecular or biological targets of these diseases. Topotecan, a topoisomerase I inhibitor, has shown single-agent activity and is now being combined with other agents, including cytarabine. The aminothiol amifostine induces responses in about 30% of patients; however, its role is still being clarified. Agents that inhibit histone deacetylase and target DNA hypermethylation, thus permitting derepression of normal genes, include 5-azacytidine, decitabine, phenylbutyrate, and depsipeptide. Arsenic trioxide has demonstrated impressive activity in acute promyelocytic leukemia and preclinical data suggest the potential for activity in MDS. UCN-01 is a novel agent that inhibits protein kinase C and other protein kinases important for progression through the G1 and G2 phases of the cell cycle. Dolastatin-10 has extremely potent in vitro activity against a variety of tumor cell lines. Since its dose-limiting toxicities include myelosuppression, it is being studied in acute myelogenous leukemia (AML) and MDS. Ras may play a role in MDS, and activation of this gene and its signaling pathways may require farnesylation. Several farnesyl transferase inhibitors are now available for study in patients with MDS. An increasing body of data suggests a possible role for angiogenesis in MDS, and several antiangiogenesis agents are in clinical trials, including thalidomide, SU5416, and anti-vascular endothelial growth factor (VEGF) antibodies. Development of new drugs and regimens will be facilitated by recently developed standardized response criteria. Future clinical trials should focus on rational combinations of these agents and others with the goal of curing patients with MDS.
很少有化疗药物在骨髓增生异常综合征（MDS）患者中显示出活性，支持性治疗仍然是标准的治疗方法。越来越多正在研发的新药针对这些疾病的特定分子或生物学靶点。拓扑替康是一种拓扑异构酶I抑制剂，已显示出单药活性，目前正在与其他药物联合使用，包括阿糖胞苷。氨磷汀可使约30%的患者产生反应；然而，其作用仍在阐明中。抑制组蛋白脱乙酰酶并靶向DNA高甲基化从而使正常基因去抑制的药物包括5-氮杂胞苷、地西他滨、苯丁酸钠和缩肽。三氧化二砷在急性早幼粒细胞白血病中已显示出令人印象深刻的活性，临床前数据表明其在MDS中也有活性的潜力。UCN-01是一种新型药物，可抑制蛋白激酶C和其他对细胞周期G1期和G2期进展重要的蛋白激酶。多拉司他汀-10在体外对多种肿瘤细胞系具有极强的活性。由于其剂量限制性毒性包括骨髓抑制，正在急性髓性白血病（AML）和MDS中进行研究。Ras可能在MDS中起作用，该基因及其信号通路的激活可能需要法尼基化。现在有几种法尼基转移酶抑制剂可用于MDS患者的研究。越来越多的数据表明血管生成在MDS中可能起作用，几种抗血管生成药物正在进行临床试验，包括沙利度胺、SU5416和抗血管内皮生长因子（VEGF）抗体。最近制定的标准化反应标准将促进新药和治疗方案的研发。未来的临床试验应侧重于这些药物与其他药物的合理联合，目标是治愈MDS患者。
