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 中国克隆性造血干细胞疾病的异质性组 它取消了未成熟前体细胞的快速诞生 其后代髓内细胞过度凋亡。这种组合 快速增殖和细胞死亡可能是临床上 高血细胞骨髓的全血细胞减少综合征，可能是 肿瘤坏死因子等细胞因子双重作用的结果 α(肿瘤坏死因子-α)、转化生长因子-β(转化生长因子-β)、 白介素1β(IL1β)和白介素1β转换酶(ICE)。 这些细胞因子(来源不明)可能同时刺激 未成熟细胞增殖，成熟细胞凋亡。通过 干扰特异性磷脂第二代的产生 信使，一系列细胞因子(肿瘤坏死因子-1)的信号通路 α、转化生长因子-β、白介素1-β)可以中断。一种药物的组合 使用己酮可可碱/环丙沙星/地塞米松(PCD) 一项试验性研究，结果是鼓励血液学和/或 多克隆造血恢复后的细胞遗传学反应， 伴随着骨髓细胞凋亡的消失 (Bm)活组织检查。以下是各种临床反应的记录 PCD表明这种抗细胞因子疗法产生了不同的 不同患者的生物学效应。无响应可能 表明要么主要的临床症状不是 细胞因子驱动或PCD抑制的细胞因子以外的细胞因子 都牵涉其中。细胞遗传学反应的差异也有类似的情况 可能是因为在有反应的患者中，细胞遗传学 标记克隆可能依赖于被抑制的细胞因子 PCD。我们提出了一个独特的临床方案，与相关的生物学 研究，特别是在使用临床反应作为一种方式方面 的不同机制进行了剖析。 MDS患者的疾病表现。一系列临床试验 提出了试验，试图进一步优化这一新的和 PCD与其他药物联合应用的独特抗细胞因子方法 常规和/或新型试剂。平行的生物学研究是 其目的是研究干细胞的性质 异常，过度的生化/分子/细胞基础 增殖/过度凋亡导致无效的造血和 细胞因子在疾病过程中产生或延续的作用 已经组织了一个强大的临床计划，有40-50个新的MDS 患者/年有资格获得临床方案和 配套的生物学研究。通过更好地理解 生物学和临床反应与无反应的原因，我们 期望开发新的治疗和预防的关键线索 在MDS的研究。

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.