CHEMOTHERAPY

理论基础：我们在新诊断的急性髓细胞白血病中的计划重点是 选择性增加药物的发展 克隆形成细胞对化疗的敏感性。这种方法 是基于这样一个概念，即增加核扩散的速度， 特别是进入S期，急性髓系白血病爆发期可敏化 细胞对当前治疗的中流砥柱(Arac、伊达比星和 氟达拉滨)，通过程序性细胞死亡(PCD)杀死细胞 通过细胞凋亡。我们已经证明了G-的结合 脑脊液、氟达拉滨和阿糖胞苷(FLAG)首次诱导CR 急性髓系白血病患者中有异常的比率超过50% 5号和/或7号染色体。尽管缓解率有所提高，但缓解 然而，在急性髓细胞白血病预后较差的亚组中，持续时间仍然较短。 这些结果表明，细胞因子如G-CSF和其他 生长调节分子，如溶血磷脂酸(LPA) 会对细胞的凋亡作用敏感地增加 化疗药物。然而，一些细胞因子可能会 干扰化疗药物对PCD的诱导。自.以来 程序性细胞死亡似乎是最终的共同机制，通过 哪些DNA损伤剂，如许多化疗药物， 包括用于治疗急性髓细胞白血病、杀伤细胞、细胞因子 而增长因素可能起到双重作用，既增加了 通过增加细胞对细胞毒药物作用的敏感性 通过抑制增殖和潜在地保护细胞 程序性细胞死亡。 假说：生长调节剂对细胞生长的影响 急性髓系白血病治疗的结果反映了增加的 对药物引起的PCD的敏感性和对细胞死亡的保护。 因此，将平衡转向PCD可能会改善患者 回应。此应用程序的目标是确定是否 细胞因子的潜在二元性效应之间的平衡 和生长因子对药物作用的增敏和抑制 确定患者的净反应，包括各种 AML的子集。此外，我们将在体外、体外确定， 并根据临床反应是否存在细胞因子的双重作用 如G-CSF和生长调节分子，如LPA Shift 急性髓系白血病细胞向PCD的转化及能否进一步促进PCD 通过添加全反式维甲酸(ATRA)或雷帕霉素， 这两种方法都被证明可以提高敏感性。 化疗引起的PCD。 具体目标：1.确定随机化是否 氟达拉滨+阿糖胞苷+伊达比星联合应用粒细胞集落刺激因子 (FAI)预后不良的AML/MDS会影响细胞增殖， 进入S期，PCD，PCD相关蛋白的表达， 对FAI的敏感性和对治疗的反应。2.确定 是否随机化添加维甲酸(全反式维甲酸 酸性维甲酸)加入FAI+G-CSF会影响细胞增殖， 进入S期，PCD，PCD相关蛋白的表达， 对FAI的敏感性和对治疗的反应。3.确定 是否增加溶血磷脂酸(LPA)的产量 利索茶碱(LSF)治疗预后良好的AML患者 Ara-C改变增殖和PCD之间的平衡，以及是否 这一改变将改善这些患者的临床结果。 4.确定雷帕霉素或干扰素是否会增强 化疗诱导急性髓系白血病细胞PCD的表达 在体外模型系统中确定调控PCD的蛋白质 这些组合是否应该在临床试验中进行评估。

I. RATIONALE: Our program in newly-diagnosed AML has focused on the development of agents to selectively increase the susceptibility of clonogenic blasts to chemotherapy. This approach is based on the concept that increasing the rate of proliferation, specifically entry into S phase, of AML blasts can sensitizes the cells to the current mainstays of therapy (araC, idarubicin and fludarabine) which kill cells by programmed cell death (PCD) through apoptosis. We have demonstrated that the combination of G- CSF, fludarabine, and ara-C (FLAG) induces, for the first time, CR rates in excess of 50% in AML patients with abnormalities of chromosomes 5 and/or 7. Despite improved CR rates, remission durations, however, remain short in poor prognosis subsets of AML. These results suggest that cytokines such as G-CSF and other growth regulatory molecules, such as lysophosphatidic acid (LPA) could increase sensitively to the apoptotic action of chemotherapeutics. However, some cytokines could potentially interfere with the induction of PCD by chemotherapeutics. Since programmed cell death appears to be the final common mechanism by which DNA damaging agents, such as many chemotherapeutics, including those used in the therapy of AML, kill cells, cytokines and growth factors may exert a dual effect both increasing sensitivity to the actions of cytotoxic drugs by increasing cell proliferation and potentially protecting cells by inhibiting programmed cell death. II. HYPOTHESIS: That the effect of growth modulators on the outcome of AML therapy reflects the balance between increased sensitivity to drug induced PCD and protection from cell death. Thus shifting the balance towards PCD may improve patient responses. The goal of this application is to determine whether the balance between the potential dualistic effect of cytokines and growth factors on sensitization and inhibition of drug action determines the net response in patients comprising the various subsets of AML. In addition, we will determine in vitro, ex vivo, and by clinical response whether the dualistic effect of cytokines such as G-CSF and growth regulatory molecules such as LPA shift AML cells towards PCD and whether PCD can be further promoted through addition of all trans retinoic acid (ATRA) or rapamycin, both of which have been demonstrated to increased the sensitivity to chemotherapy-induced PCD. III. SPECIFIC AIMS: 1. To determine whether randomization of addition of G-CSF to therapy with fludarabine + ara-C + idarubicin (FAI) in poor prognosis AML/MDS will affect cell proliferation, entry into S phase, PCD, expression of proteins involved in PCD, sensitivity to FAI, and response to therapy. 2. To determine whether randomization of addition of retinoids (all trans retinoic acid ATRA) added to FAI + G-CSF will affect cell proliferation, entry into S phase, PCD, expression of proteins involved in PCD, sensitivity to FAI, and response to therapy. 3. To determine whether increasing the production of lysophosphatidic acid (LPA) with lisofylline (LSF) in good prognosis AML patients receiving ara-C alters the balance between proliferation and PCD and whether this alteration will improve clinical outcome in these patients. 4. To determine whether rapamycin or IFN will enhance chemotherapy-induced PCD in AML cells by altering expression of proteins regulating PCD in in vitro model systems to determine whether these combinations should be assessed in clinical trials.