Bortezomib and Idarubicin in the Treatment of AML

硼替佐米和伊达比星治疗 AML

• 批准号: 6887118
• 负责人: Dianna S Howard
• 金额: $ 25.76万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887118
• 关键词: acute myelogenous leukemia; adult human (21+); anthracyclines; antineoplastics; apoptosis; clinical research; clinical trial phase I; clinical trial phase II; combination chemotherapy; dosage; drug screening /evaluation; human old age (65+); human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer relapse /recurrence; nuclear factor kappa beta; p53 gene /protein; patient oriented research; protease inhibitor; proteasome

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a clonal, malignant disease of hematopoietic cells, characterized by the proliferation of abnormal blast cells and impaired hematopoiesis. While younger patients with favorable cytogenetics have increasingly favorable outcomes with dose intensive chemotherapy, they represent a distinct minority of patients with this disease. Patients with unfavorable cytogenetics, advanced age (>=60), and antecedent hematologic disorders have a decreased incidence of complete remission; even in those who achieve an initial remission, the majority relapse and survival is poor. Clearly this is a patient population for whom novel therapies are needed. Studies from our laboratory have demonstrated that the combination of the proteasome inhibitor, bortezomib, with the anthracycline, idarubicin, at concentrations readily achievable in vivo can rapidly induce apoptosis in primary human AML cells in vitro. Studies from our laboratory have demonstrated that apoptosis induced in this fashion correlates with several specific changes in primary AML cells. Following treatment with bortezomib and idarubicin strong inhibition of NF-kappaB is rapidly observed, indicating inhibition of important survival signals. In addition, levels of p53 protein are strongly increased in treated AML cells, suggesting p53 mediated changes in gene expression might be involved in the apoptosis induced by this combination. Based on our observations we propose a phase I and II clinical trial with the novel agent, bortezomib, and idarubicin given to newly diagnosed, elderly or relapsed AML patients. Monitoring for in vivo induction of apoptosis, as well as, important correlative studies assaying for inhibition of NF-kappaB and increased p53 expression are proposed. We anticipate that with this novel treatment regimen we will observe potent anti-leukemic activity and complete clinical remissions.

描述(申请人提供)：急性髓系白血病(AML)是一种克隆性、恶性的造血细胞疾病，以异常原始细胞增殖和造血功能受损为特征。虽然细胞遗传学良好的年轻患者接受剂量密集化疗的结果越来越好，但他们在这种疾病的患者中占明显的少数。细胞遗传学不良、高龄(&gt；=60)和既往血液病的患者完全缓解的发生率较低；即使在那些获得初步缓解的患者中，大多数患者的复发和存活率也很低。显然，这是一个需要新疗法的患者群体。我们实验室的研究表明，蛋白酶体抑制剂Bortezomib与蒽环类药物伊达比星在体内容易达到的浓度相结合，可以在体外快速诱导原代培养的人AML细胞凋亡。我们实验室的研究表明，以这种方式诱导的细胞凋亡与原代AML细胞的几个特定变化有关。在硼替佐米和伊达比星治疗后，迅速观察到对NF-kappaB的强烈抑制，这表明重要的生存信号被抑制。此外，经P53处理的AML细胞中P53蛋白水平显著升高，提示P53介导的基因表达变化可能参与了这种联合作用诱导的细胞凋亡。基于我们的观察，我们建议对新诊断的、老年或复发的AML患者使用新型药物Bortezomib和伊达比星进行I期和II期临床试验。提出了体内诱导细胞凋亡的监测，以及重要的相关研究，分析抑制核因子-kappaB和增加p53的表达。我们预计，通过这种新的治疗方案，我们将观察到强大的抗白血病活性，并完成临床缓解。