NOVEL THERAPEUTIC STRATEGIES IN MYELODYSPLASTIC SYNDROME

许多患者的骨髓增生异常综合征(MDS)的特点是 外周血细胞减少伴细胞或细胞减少 骨髓。虽然一部分患者最终会患上急性白血病， 40%-50%的患者死于出血或感染性疾病 并发症。令人满意的治疗，以造血干细胞的形式 移植，只适用于一小部分患者。新的 治疗方式是必要的。最近的研究表明，增加的表达 肿瘤坏死因子-α等造血负性调节因子 MDS骨髓中的高凋亡率(程序性细胞死亡)。初步 研究表明，通过阻断阴性可以改善造血。 或者通过消除这些信号的细胞来源。这个 申请者建议1)进行一系列临床试验，以确定 TNFR：Fc(可溶性肿瘤坏死因子受体)、抗胸腺细胞球蛋白(ATG)和 抗T细胞因子)和Flt3配体(一种早期激活的细胞因子)单独和在 联合用药改善外周血细胞减少和稳定造血功能 MDS患者；2)开展骨髓的体外/体外研究 患者参加这些试验，以确定其形态、免疫表型、 肿瘤坏死因子-α、Fas和Fas-L的表达与细胞遗传学 治疗前后的异常及其与体外/体外的相关性 体内治疗反应的参数和反应的“质量”；3) 利用新的探针和试剂开发更多的治疗方法。 预计这些研究将产生数据，指导选择 患者对未来的具体方案。治疗的最优化，反过来， 应减少与MDS相关的发病率和死亡率，并改善 MDS患者的生活质量。

Myelodysplastic syndrome (MDS) in many patients is characterized by peripheral blood cytopenias in the presence of cellular or hypocellular marrow. While a proportion of patients will eventually develop acute leukemia, 40 percent-50 percent of patients die with hemorrhagic or infectious complications. Satisfactory therapy, in the form of hemopoietic stem cell transplantation, is available only to a small proportion of patients. New treatment modalities are needed. Recent studies show increased expression of negative regulators of hemopoiesis such as tumor necrosis factor (TNF)-alpha and a high rate of apoptosis (programmed cell death) in MDS marrow. Preliminary investigations suggest that hemopoiesis can be improved by blocking negative regulatory signals or by eliminating the cellular source of those signals. The applicants propose to 1) conduct a series of clinical trials to determine the efficacy of TNFR:Fc (a soluble TNF receptor), antithymocyte globulin (ATG, an anti-T-cell agent), and flt3-ligand (an early activating cytokine) alone and in combination, in improving peripheral cytopenias and stabilizing hemopoiesis in patients with MDS; 2) to carry out in vitro/ex vivo studies on marrow from patients enrolled in those trials to characterize morphology, immunophenotype, expression of TNF-alpha, Fas and Fas-ligand, as well as cytogenetic abnormalities, before and after therapy and to correlate in vitro/ex vivo parameters with in vivo treatment responses and "quality" of response; 3) to develop additional treatment approaches utilizing new probes and reagents. These studies are expected to generate data that will guide the selection of patients for future specific protocols. Optimization of therapy, in turn, should reduce morbidity and mortality associated with MDS and improve the quality of life of patients with MDS.