CLINICAL AND BIOLOGICAL STUDIES IN MYELODYSPLATIC SYNDROMES

骨髓增生异常综合征（MDS）是一种高度复杂的， 克隆性造血干细胞疾病的异质性群体 不成熟前体的快速细胞出生被取消， 其后代的髓内过度凋亡。 这种组合 快速增殖和细胞死亡可能解释了临床 尽管骨髓细胞增多，但全血细胞减少综合征可能是一种 肿瘤坏死因子等细胞因子双重作用的结果 α（TNF-α），转化生长因子β（TGF-β）， 白细胞介素1 β（IL 1 β）和IL 1 β转化酶（ICE）。 这些细胞因子（来源不明）可能同时刺激 未成熟细胞的增殖和成熟细胞的凋亡。 通过 干扰特异性磷脂的产生， 信使，细胞因子（TNF-α）级联的信号通路， TGF-α、TGF-β、IL-1 β）可以被中断。 药物的组合 使用喷替福林/环丙沙星/地塞米松（PCD）， 一项试点研究，并导致了令人鼓舞的血液学和/或 细胞遗传学应答与多克隆造血的恢复， 伴随着骨髓细胞凋亡的消失 (BM)活组织检查 在以下情况下观察到各种临床反应： PCD表明这种抗细胞因子疗法产生不同的 不同患者的生物学效应。 无反应性可能 表明主要临床综合征不是 细胞因子驱动的或细胞因子以外的PCD抑制 参与其中 细胞遗传学反应差异的类似情况 因为在有反应的患者中，细胞遗传学 标记的克隆可能依赖于细胞因子抑制， PCD。 我们提出了一个独特的临床计划， 研究，特别是在使用临床反应作为一种方式方面， 剖析不同的机制， MDS患者中的疾病表现。 一系列临床 提出了尝试进一步优化这种新的且 独特的抗细胞因子的方法，通过结合PCD与其他 常规和/或新型试剂。 平行生物学研究是 提出的目的是研究干细胞的性质， 异常，过度的生物化学/分子/细胞基础 增殖/过度凋亡导致无效造血， 细胞因子在产生或维持疾病过程中的作用。 一个强大的临床计划已经组织了40-50个新的MDS 有资格纳入临床方案的患者/年 生物学研究。 更好地了解 生物学和临床反应与无反应的原因，我们 希望开发新的治疗和预防的关键线索 MDS研究

The myelodysplastic syndromes (MDS) are a highly complex, heterogeneous group of clonal hemopoietic stem cell disorders in which the rapid cell-birth of immature precursors is cancelled by excessive intramedullary apoptosis of their progeny. This combination of rapid proliferation and cell death may account for the clinical syndrome of pancytopenia despite hypercellular marrows and may be a result of the dual actions of cytokines such as tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin 1beta (IL1beta) and IL1beta converting enzyme (ICE). These cytokines (source unknown) may simultaneously stimulate proliferation in the immature cells and apoptosis in mature cells. By interfering with the generation of specific phospholipid second messengers, the signalling pathway for a cascade of cytokines (TNF- alpha, TGF-beta, IL1beta) can be interrupted. A combination of drugs using pentoxifylline/ciprofloxacin/dexamethasone (PCD) were used in a pilot study and resulted in encouraging hematologic and/or cytogenetic responses with resumption of polyclonal hemopoiesis, accompanied by the disappearance of apoptosis from bone marrow (BM) biopsies. A variety of clinical responses were noted following PCD suggesting that this anti-cytokine therapy produces different biological effects in different patients. Non-responsiveness may indicate that either the predominant clinical syndrome was not cytokine-driven or that cytokines other than those suppressed by PCD were involved. A similar case for differences in cytogenetic responses could be made since in the responding patients, the cytogenetically marked clone may have been dependent on cytokines suppressed by PCD. We propose a unique clinical program with correlative biologic studies, unique especially in terms of using clinical response as a way of dissecting the different mechanisms underlying the differences in the manifestations of disease among MDS patients. A series of clinical trials are proposed which attempt to further optimize this new and unique anti-cytokine approach by combining PCD with other conventional and/or novel agents. Parallel biological studies are proposed which are designed to investigate the nature of the stem cell abnormality, the biochemical/molecular/cellular basis for the excessive proliferation/excessive apoptosis leading to ineffective hemopoiesis and the role of cytokines in producing or perpetuating the disease process. A strong clinical program has been organized with 40-50 new MDS patients/year eligible for accrual onto the clinical protocols and for the companion biological studies. With better understanding of the biology and reasons for clinical response versus non-response, we expect to develop critical leads for novel therapeutic and preventive studies in MDS.