Plant-derived differentiation agents for AML

用于 AML 的植物衍生分化剂

• 批准号: 7481973
• 负责人: Mukesh Kumar Agarwal
• 金额: $ 14.25万
• 依托单位: INVENIO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-08 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481973
• 关键词: Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Adult; Adverse effects; Age; Alkaloids; American; Amino Acids; Amyotrophic Lateral Sclerosis; Anti-Infective Agents; Anti-inflammatory; Antineoplastic Agents; Aplastic Anemia; Area; Atropine; Berry; Biological; Biological Factors; Biological Models; Biology; Bone Marrow; British; Butyric Acid; Butyric Acids; Caffeine; Cell Differentiation process; Cell Maturation; Cells; Central Nervous System Stimulants; Chemical Structure; Chemicals; China; Chinese Herbs; Clinical; Clinical Trials; Cocaine; Codeine; Collaborations; Collection; Combinatorial Chemistry Techniques; Condition; Country; Data; Development; Differentiation Inducer; Differentiation Therapy; Disease; Diuretics; Drug Delivery Systems; Drug Kinetics; Elderly; Engraftment; Ensure; Exhibits; Familiarity; Fruit; GABA Antagonists; Goals; Growth; Human; In Vitro; Individual; International; Knowledge; Lead; Left; Leukemic Cell; Libraries; Life; Malaria; Malignant - descriptor; Malignant Neoplasms; Marketing; Measures; Medicine; Morbidity - disease rate; Morphine; Multiple Sclerosis; Mus; Mydriasis; Myeloid Cells; Natural regeneration; Neurologic; Nicotine; Nitrogen; Numbers; Pain; Parents; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plant Roots; Plants; Play; Poliomyelitis; Population; Preclinical Drug Development; Preclinical Drug Evaluation; Proliferating; Public Health; Quinine; Range; Reporting; Research; Role; Russia; Sampling; Scopolamine; Screening procedure; Securinega; Seeds; Seizures; Source; Standards of Weights and Measures; Stem cells; Structure; Testing; Therapeutic; Therapeutic Uses; Thinking; Toxic effect; Treatment Protocols; Tretinoin; United States; Vinblastine; Vincristine; Work; Xenograft Model; analog; anti-cancer therapeutic; anticancer research; base; cancer therapy; chemotherapy; cytotoxicity; drug development; drug discovery; experience; high throughput screening; improved; in vivo; interest; leukemia; mortality; mouse model; nervous system disorder; novel; novel therapeutics; older patient; outcome forecast; pre-clinical; programs; securinine; sedative; small molecule; small molecule libraries; stem; subcutaneous; success; technological innovation; tumor

DESCRIPTION (provided by applicant): Plant-derived compounds, particularly alkaloids, have historically been a successful source of currently used therapeutics. Recently, a plant-derived alkaloid was identified that is a potent acute myeloid leukemia (AML) differentiation-inducing compound. Differentiation therapy for AML holds significant promise in leading to more efficacious and less toxic therapies. Though AML is one of the most common forms of leukemia in adults, the 5 year survival is less than 20-50% in adults and significantly lower in the elderly. The remarkable success in treating one relatively uncommon subset of AML, acute promyelocytic leukemia, with all trans-retinoic acid (ATRA) illustrates the great promise for differentiation therapy. Utilizing ATRA, the presumed cure of 75-85% of patients is possible. ATRA's remarkable success stems from the fact that AML is a disease characterized by the arrest of differentiation of immature myeloid cells. ATRA overcomes this block in differentiation by forcing leukemic cells to mature. After leukemic cells undergo terminal differentiation, they lose their ability to proliferate. The aims of this phase I project are to 1) demonstrate the promise of a novel plant-derived alkaloid in a mouse xenograft model system 2) demonstrate the activity of this compound and its analogues in vitro and 3) to identify novel plant-derived alkaloids with potent AML differentiation activity. As differentiation therapies are able to treat leukemia without the necessity for overt cytotoxicity, this work has the potential to lead to a more efficacious, less toxic, and better tolerated therapy for patients with AML. PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health as its main objective is to identify and develop novel therapeutics for patients with Acute Myeloid Leukemia that are better tolerated and more efficacious. As the prognosis for most patients with AML is currently poor, there is a significant need for new therapies.

描述（由申请人提供）：植物衍生化合物，特别是生物碱，历来是目前使用的治疗药物的成功来源。最近，一种植物源性生物碱被发现是一种有效的急性髓性白血病（AML）分化诱导化合物。AML的分化治疗在导致更有效和更少毒性的治疗方面具有重要的前景。虽然AML是成人最常见的白血病形式之一，但成人的5年生存率低于20-50%，老年人的5年生存率更低。全反式维甲酸（ATRA）在治疗急性髓细胞白血病（AML）中一个相对罕见的亚型——急性早幼粒细胞白血病方面取得了显著的成功，这说明了分化治疗的巨大前景。使用ATRA， 75-85%的患者可能被治愈。ATRA的显著成功源于AML是一种以未成熟骨髓细胞分化受阻为特征的疾病。ATRA通过迫使白血病细胞成熟来克服这种分化障碍。白血病细胞经过终末分化后，就失去了增殖能力。这个I期项目的目的是：1)在小鼠异种移植模型系统中证明一种新型植物源性生物碱的前景；2)在体外证明该化合物及其类似物的活性；3)鉴定具有有效AML分化活性的新型植物源性生物碱。由于分化疗法能够治疗白血病而不需要明显的细胞毒性，这项工作有可能为AML患者带来更有效、毒性更小、耐受性更好的治疗方法。公共卫生相关性：该项目与公共卫生高度相关，因为其主要目标是确定和开发耐受性更好、更有效的急性髓系白血病患者的新疗法。由于目前大多数AML患者的预后较差，因此迫切需要新的治疗方法。

项目成果

Securinine, a myeloid differentiation agent with therapeutic potential for AML.

• DOI: 10.1371/journal.pone.0021203
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gupta K;Chakrabarti A;Rana S;Ramdeo R;Roth BL;Agarwal ML;Tse W;Agarwal MK;Wald DN
• 通讯作者: Wald DN