NOVEL RETINOIDS FOR LEUKEMIA THERAPY

用于白血病治疗的新型维A酸

• 批准号: 2895885
• 负责人: DONALD D MUCCIO
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895885
• 关键词: 13 cis retinoate; acute myelogenous leukemia; apoptosis; cell proliferation; child (0-11); clinical research; colony stimulating factor; cytotoxicity; disease /disorder model; drug design /synthesis /production; drug hypersensitivity; drug metabolism; drug resistance; drug screening /evaluation; human subject; human therapy evaluation; isomer; laboratory mouse; neoplasm /cancer chemotherapy; neoplastic cell; pediatric pharmacology; pharmacokinetics; receptor expression; retinoid binding proteins; vitamin therapy

DESCRIPTION: Retinoic acid (RA) is the major clinically useful therapy for two leukemias, acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML). In APL, all-trans-RA induces complete remission in most patients, but relapse is common due to the rapid development of RA resistance and induction of RA toxicity. Agents which are more effective and do not lead to resistance are needed. Some children with JMML are stabilized with 13-cis-RA until they can receive bone marrow transplants at an older age, but more effective agents are needed to extend stabilization to a larger percentage of patients. This project will develop new retinoids that are more effective than RA for the therapy of APL and JMML. The new drugs will be derived from a unique class of retinoids that were developed at UAB by the investigator and co-investigator of this application. Two UAB8 isomers from this class were shown to be more effective than RA in an APL model and as effective as RA in a JMML model, yet they were less toxic and exhibited a more favorable pharmacological profile. They will first explore more fully the activity of UAB8 and then we will optimize the structure of UAB retinoids to provide the best clinical candidates for APL and JMML therapy. To accomplish this goal, a team of scientists with backgrounds in retinoid research has been assembled, including medicinal chemists, clinical oncologists, biochemists, pharmacologists. This team will use a broadly based approach involving a) synthesis; b) nuclear receptor binding/transactivational assays; c) in vitro assays (induction of differentation and/or apoptosis in APL cells, and inhibition of murine and human JMML colony formation; d) pharmacology studies on the self-induction of metabolism in mice and e) in vivo evaluation in a JMML mouse model.

描述：视黄酸（RA）是用于临床上主要有用的疗法 两个白血病，急性寄生虫细胞白血病（APL）和少年 脊髓细胞性白血病（JMML）。 在APL中，全型trans-ra诱导完整 大多数患者的缓解，但由于迅速而复发很常见 RA耐药性的发展和RA毒性的诱导。 代理 需要更有效，并且不需要阻力。 有些孩子 JMML用13-CIS-RA稳定，直到可以接收骨髓 年龄较大的移植物需要更有效的代理来扩展 稳定到较大比例的患者。 这个项目将开发 对于APL和APL治疗，比RA更有效的新类视黄素 JMML。 新药将来自独特的类视网膜类似 由研究者和共同投资者在UAB上开发 应用。 该课程的两个UAB8异构体被证明更多 在APL模型中比RA有效，在JMML模型中与RA一样有效， 但是它们的毒性较小，并且表现出更有利的药理 轮廓。 他们将首先更全面地探索UAB8的活动，然后 我们将优化UAB类维生素的结构，以提供最佳的临床 APL和JMML治疗的候选人。 为了实现这一目标，一个团队 具有类视感研究背景的科学家已经组装了 包括药物学家，临床肿瘤学家，生物化学家， 药理学家。 该团队将使用涉及广泛的方法A） 合成; b）核受体结合/反式激活测定； c）体外 测定（在APL细胞中诱导区分和/或凋亡，以及 抑制鼠和人类JMML菌落形成； D）药理学 关于小鼠新陈代谢的自我诱导和E）体内的研究 在JMML鼠标模型中进行评估。