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）：植物衍生的化合物，特别是生物碱，历来是当前使用的治疗剂的成功来源。最近，一种植物来源的生物碱被鉴定为一种有效的急性髓系白血病 (AML) 分化诱导化合物。 AML 的分化治疗在带来更有效、毒性更小的治疗方法方面具有重大前景。尽管 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%，老年人的生存率明显更低。使用全反式视黄酸 (ATRA) 治疗一种相对罕见的 AML 亚型（急性早幼粒细胞白血病）取得了显着成功，这说明了分化治疗的巨大前景。利用 ATRA，预计可以治愈 75-85% 的患者。 ATRA 的显着成功源于以下事实：AML 是一种以未成熟骨髓细胞分化停滞为特征的疾病。 ATRA 通过迫使白血病细胞成熟来克服这种分化障碍。白血病细胞经历终末分化后，就会失去增殖能力。该第一阶段项目的目标是 1) 在小鼠异种移植模型系统中证明新型植物源生物碱的前景 2) 证明该化合物及其类似物的体外活性 3) 鉴定新型植物源生物碱具有有效的 AML 分化活性。由于分化疗法能够治疗白血病而无需明显的细胞毒性，因此这项工作有可能为 AML 患者提供更有效、毒性更小、耐受性更好的治疗方法。 公共健康相关性：该项目与公共健康高度相关，因为其主要目标是为急性髓性白血病患者寻找和开发耐受性更好、更有效的新疗法。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