MOLECULAR DETERMINANTS OF CHEMOTHERAPY RESISTANCE

虽然诱导联合化疗方案用于急性 骨髓性白血病（AML）与完全 诱导缓解频率为75%，仅占总数的20%左右 每年有许多AML患者治愈了他们的疾病， 常规剂量联合化疗。AML的具有 平衡易位[倒位l 6和t（8;21）]已经被 治愈率超过60% t（15; 17）是 与中间预后相关。预后不良 亚群与5号染色体的单体性有关， 7、t（9;22）和8号三体。这些病人几乎都不能 经常规剂量联合化疗治愈。的基因 在良好预后亚组的易位断点处 包括t（15;17）中的MIL RAR α和CBF的嵌合体， t（8;21）和逆16子集中的α和β， 分别这些子集，尤其是反转16，属于 所有肿瘤状态中最敏感的疾病。单个 阿糖胞苷（Ara-C）可以治愈这种患者 亚群，而不根除正常的骨髓细胞。这 这表明这些倒位16的AML细胞更容易受到 化疗诱导的细胞死亡比正常细胞，而 预后不良的亚群是所有抗肿瘤药物中最耐药的。 肿瘤，通常甚至在超致命水平的 化疗 该项目旨在确定AML中的分子变化 对化疗反应起主导作用的细胞 和生存，并将这些信息应用于发展 治疗这种疾病的新方法这个项目是 （一）在前几个供资年度的工作情况 赠款揭示了水平和功能状态的变化， 生长因子诱导途径中的蛋白质（Rb、p53和WAF-1）， 1)这预示着对治疗的反应降低， （2）WAF-1被P53激活抑制增殖 在AML细胞中，与化疗耐药性有关 细胞遗传学改变的组合 AML患者细胞中的分子变化定义了一种 一组标志物，不仅可用于预测敏感性， 或对治疗的抵抗，但也要了解的机制， （4）在突变点的基因的同一性， 大多数平衡易位已被确定;和 (5)基因改造可用于开发治疗 基于逆转这些遗传变化的干预措施， AML细胞，从而抑制AML的肿瘤表型， 急性髓细胞白血病细胞或增加其对化疗的敏感性。对 基于这些发现，我们建议使用治疗 结果数据和遗传变化的分子分析， 缓解者和非缓解者，以确定AML中的变化 细胞在产生高水平和低水平的 对化疗的敏感性低。我们亦会研究如何利用 分子和遗传学方法修饰AML细胞， 抑制耐药表型作为治疗的主要手段。 这些信息的最终应用是使用这些 替代反应标志物，以将患者分配到 适当的治疗。

Although induction combination chemotherapy regimens for acute myelogenous leukemia (AML) are associated with a complete remission induction frequency of 75 %, only about 20% of the total number of AML patients per year are cured of their disease with conventional dose combination chemotherapy alone. AML with balanced translocations [inversion l6 and t(8;21)] have been associated with cures in excess of 60%. The t(15; 17) has been associated with an intermediate prognosis. The poor prognosis subsets have been associated with monosomies of chromosomes 5 and 7, t(9;22), and trisomy 8. Almost none of these patients can be cured with conventional dose combination chemotherapy. The genes at the translocation breakpoints in the good prognosis subsets include the MIL RARalpha in t(15;17), and the chimeras of CBF alpha and beta in the t(8;21) and the inversion 16 subsets, respectively. These subsets, especially inversion 16, are among the most sensitive diseases of all the neoplastic states. A single drug, cytosine arabinoside (Ara-C), can cure patients with this subset, while not eradicating the normal myeloid cells. This suggests that these inversion 16 AML cells are more vulnerable to chemotherapy-induced cell death than are normal cells, whereas the poor prognosis subsets are among the most resistant of all of the neoplasms, often surviving even super lethal levels of chemotherapy. This project is designed to identify the molecular changes in AML cells which exert a dominant effect on response to chemotherapy and on survival, and to apply that information to the development of novel approaches to therapy of this disease. This project is based on the following data: (I) Work in prior funding years of the grant revealed changes in the levels and functional states of proteins in the growth factor induction pathway (Rb, p53 and WAF- 1) which are predictive of decreased response to therapy and survival; (2) WAF-1 is activated by P53 suppresses proliferation in AML cells, and is associated with resistance to chemotherapy induced apoptosis; (3) The combination of the cytogenetic changes and the molecular changes in the cells of AML patients define a set of markers which can be used to not only predict sensitivity or resistance to therapy but also to understand the mechanisms of this resistance; (4) The identity of genes at the breakpoints of the majority of balanced translocations have been identified; and (5) Genetic modification can be used to develop therapeutic interventions based on the reversal of these genetic changes in the AML cell so as to either suppress the neoplastic phenotype of the AML cell or to increase their sensitivity to chemotherapy. On the basis of these findings, we have proposed to use therapy outcome data and molecular analysis of genetic changes in responders and nonresponders to identify the changes within AML cells that are exerting a dominant effect in generating a high and low sensitivity to chemotherapy. We will also study ways of using molecular and genetic methods to modify AML cells so as to suppress the resistance phenotype as a primary means of therapy. The ultimate application of this information is to use these surrogate markers of response to allocate patients to the most appropriate therapy.