A novel ellipticine analog as a therapeutic candidate for acute myeloid leukemia

一种新型玫瑰树碱类似物作为急性髓系白血病的治疗候选药物

• 批准号: 7746700
• 负责人: Mukesh Kumar Agarwal
• 金额: $ 15.38万
• 依托单位: CLEVELAND LEUKEMIA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-13 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746700
• 关键词: Acute; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Address; Adult; Adverse effects; Animals; Attention; Benign; Biological Models; Biology; Bone Marrow; Cell Death; Cell Line; Cell Maturation; Cells; Colon Carcinoma; Development; Differentiation Inducer; Differentiation Therapy; Disease; Drug Delivery Systems; Ellipticines; Exhibits; Functional disorder; HL60; Hematopoietic; Hemolysis; Immunophenotyping; In Vitro; Leukemic Cell; Libraries; Life; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Modeling; Morphology; Mus; Myelogenous; Myeloid Cells; Myeloid Leukemia; Natural regeneration; Nitroblue Tetrazolium; Patients; Phase; Proliferating; Public Health; Quality of life; Safety; Sampling; Source; Stem cells; Therapeutic; Therapeutic Agents; Toxic effect; Treatment Protocols; Tretinoin; Work; analog; base; cancer cell; cell growth; chemotherapeutic agent; chemotherapy; ellipticine; improved; in vivo; leukemia; malignant breast neoplasm; mouse model; novel; public health relevance; subcutaneous; tumor; tumor growth

DESCRIPTION (provided by applicant): Existing therapeutic agents for Acute Myeloid Leukemia (AML) are inadequate to due poor efficacy and severe side effects. This is especially a problem in adults where the 5 year survival is less than 20-50%. Differentaition therapy for AML holds significant promise in leading to more efficacious and less toxic therapies. AML is a disease characterized by the arrest of differentiation of immature myeloid cells. After leukemic cells undergo terminal differentiation, they lose their ability to proliferate. The potential of differentiation therapy has been demonstrated by the use of the differentiation agent, ATRA, for one relatively uncommon subset of AML, acute promyelocytic leukemia. With the use of ATRA 75-85% of acute promyelocytic leukemia patients can now be cured. We have recently identified a novel differentiation-inducing agent, CLT731, that exhibits potent in vitro leukemia differentiation-inducing activity and preliminary evidence of mouse in vivo activity. CLT731 is an analogue of ellipticine, an agent that has perviously been found to have anti-tumor activity but also exhibits high toxicity. As CLT731 has preferential activity on leukemic cells, it appears to have a significantly reduced toxicity profile. The aims of this phase I project are to 1) demonstrate the promise of a CLT731 in mouse AML model systems 2) demonstrate the activity of this compound on patient samples in vitro and 3) to assess its potential toxicities. Due to the enormous need for novel AML therapeutics, especially agents with reduced toxicity, this work has the potential to improve the quality of life for patients with AML. PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health as its main objective is to develop a novel therapy for patients with Acute Myeloid Leukemia that is both efficacious and has low toxicity. As the current AML therapeutics have low efficacy and high toxicities, there is a significant need for new therapies for AML.

描述（由申请人提供）：现有的急性髓系白血病（AML）治疗药物由于疗效差和严重副作用而不足。这在5年存活率低于20- 50%的成年人中尤其是一个问题。AML的分化治疗在导致更有效和毒性更小的治疗方面具有重要的前景。AML是一种以未成熟骨髓细胞的分化停滞为特征的疾病。在白血病细胞经历终末分化后，它们失去了增殖能力。分化治疗的潜力已被证明是通过使用分化剂，全反式维甲酸，一个相对罕见的子集的急性髓细胞白血病，急性早幼粒细胞白血病。随着ATRA的使用，75-85%的急性早幼粒细胞白血病患者现在可以治愈。我们最近发现了一种新的分化诱导剂，CLT 731，表现出强大的体外白血病分化诱导活性和小鼠体内活性的初步证据。CLT 731是椭圆藤碱的类似物，椭圆藤碱是一种经常被发现具有抗肿瘤活性但也表现出高毒性的药剂。由于CLT 731对白血病细胞具有优先活性，因此它似乎具有显著降低的毒性特征。该I期项目的目的是1）证明CLT 731在小鼠AML模型系统中的前景，2）证明该化合物对体外患者样品的活性，3）评估其潜在毒性。由于对新型AML治疗药物的巨大需求，特别是毒性降低的药物，这项工作有可能改善AML患者的生活质量。 公共卫生相关性：该项目与公共卫生高度相关，因为其主要目标是为急性髓性白血病患者开发一种既有效又低毒的新疗法。由于目前的AML疗法具有低疗效和高毒性，因此对AML的新疗法存在显著需求。