MOLECULAR DETERMINANTS OF CHEMOTHERAPY RESISTANCE

化疗耐药性的分子决定因素

• 批准号: 6269500
• 负责人: ALBERT B DEISSEROTH
• 金额: $ 15.72万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-05 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269500
• 关键词: acute myelogenous leukemia; apoptosis; biomarker; cell growth regulation; chromosome translocation; drug resistance; human tissue; leukopoiesis; molecular oncology; neoplasm /cancer chemotherapy; neoplasm /cancer diagnosis; neoplasm /cancer genetics; prognosis; tumor suppressor genes

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.

尽管急性诱导组合化疗方案 髓质白血病（AML）与完整的 缓解诱导频率为75％，仅占总数的20％ 每年AML患者数量可以治愈其疾病 常规剂量组合化疗。 AML与 平衡易位[反转L6和T（8; 21）] 与超过60％的治疗相关。 t（15; 17）已经 与中间预后有关。预后不良 子集与染色体5和 7，t（9; 22）和三体术。这些患者几乎都不是 用常规剂量组合化疗固化。基因 在良好预后子集中的易位断点 在t（15; 17）和CBF的嵌合体中包括Mil Raralpha t（8; 21）和反转​​16个子集中的alpha和beta， 分别。这些子集，尤其是反转16，是 所有肿瘤状态中最敏感的疾病。一个 药物，胞嘧啶阿拉伯糖苷（ARA-C），可以治愈患者 子集，而没有消除正常的髓样细胞。这 建议这些反转16 AML单元更容易受到影响 化学疗法诱导的细胞死亡比正常细胞，而 预后不良亚群是所有的最具抵抗力之一 肿瘤，通常甚至可以生存 化学疗法。 该项目旨在确定AML的分子变化 对对化学疗法反应产生主要作用的细胞 以及生存，并将这些信息应用于开发 新型治疗这种疾病的方法。这个项目是 基于以下数据：（i）在以前的资金数年中工作 该赠款揭示了其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）可以预测对治疗的反应减少和 生存； （2）通过p53激活WAF-1会抑制增殖 在AML细胞中，与化学疗法的抗性有关 诱导凋亡； （3）细胞遗传学变化的组合 AML患者细胞的分子变化定义A 一组可用于预测灵敏度的标记 或抵抗治疗，但也了解 这种抵抗； （4）基因在断点 已经确定了大多数平衡的易位；和 （5）遗传修饰可用于发展治疗 基于这些遗传变化的逆转干预措施 AML细胞以抑制肿瘤表型 AML细胞或增加其对化学疗法的敏感性。在 这些发现的基础，我们建议使用治疗 结果数据和遗传变化的分子分析 响应者和非反应者以识别AML中的更改 在产生高和高的细胞中发挥主要作用的细胞 对化学疗法的敏感性低。我们还将研究使用的方法 修饰AML细胞的分子和遗传方法，以便 抑制抗性表型作为主要治疗手段。 此信息的最终应用是使用这些 对患者分配最多的反应的替代标记 适当的疗法。