CHEMOTHERAPY

I.理由：我们在新诊断的AML中的项目重点是 开发选择性地增加 克隆形成母细胞对化疗的敏感性。这种方法 是基于这样一个概念，即增加扩散率， 特别是进入S期，AML母细胞可以敏感地 细胞到目前的主要治疗（araC，idarcadine和 氟达拉滨），其通过程序性细胞死亡（PCD）杀死细胞 通过凋亡。我们已经证明，G- CSF、氟达拉滨和阿糖胞苷（FLAG）首次诱导CR 在AML患者中， 染色体5和/或7。尽管CR率提高，但缓解 然而，在预后不良的AML亚群中，持续时间仍然很短。 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） 可以增加敏感的凋亡作用， 化疗药物然而，一些细胞因子可能 干扰化疗药物诱导PCD。以来 程序性细胞死亡似乎是最终的共同机制， DNA损伤剂，例如许多化疗剂， 包括用于治疗AML的那些、杀伤细胞、细胞因子 和生长因子可能发挥双重作用， 通过增加细胞对细胞毒性药物作用的敏感性， 增殖和潜在地通过抑制 程序性细胞死亡 二.假设：生长调节剂对生长的影响 AML治疗的结果反映了增加的 对药物诱导的PCD的敏感性和对细胞死亡的保护。 因此，将平衡转向PCD可以改善患者 应答此应用程序的目标是确定是否 细胞因子潜在的双重作用之间的平衡 和生长因子对药物作用的增敏和抑制作用 确定患者的净反应，包括各种 AML的子集。此外，我们将确定在体外，离体， 以及临床反应是否是细胞因子的双重作用 如G-CSF和生长调节分子如LPA移位 AML细胞向PCD的分化以及PCD是否可以进一步促进 通过加入全反式维甲酸（ATRA）或雷帕霉素， 这两种方法都被证明可以提高 化疗诱导的PCD 三.具体目标：1.为了确定是否随机化 在氟达拉滨+阿糖胞苷+依达替尼治疗中添加G-CSF (FAI)预后不良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.以确定 是否随机添加类维生素A（全反式维甲酸 加入FAI + G-CSF中的酸性ATRA）将影响细胞增殖， 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.以确定 是否增加溶血磷脂酸（LPA）的产生， 与异丙茶碱（LSF）在预后良好的AML患者接受 ara-C改变了增殖和PCD之间的平衡， 这种改变将改善这些患者的临床结果。 4.为了确定雷帕霉素或IFN是否会增强 化疗诱导的急性髓细胞白血病细胞的PCD，通过改变 在体外模型系统中调节PCD的蛋白，以确定 是否应该在临床试验中评估这些组合。

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.