NOVEL RETINOIDS FOR LEUKEMIA THERAPY

描述：维甲酸（RA）是临床上主要的有效治疗药物， 两种白血病，急性早幼粒细胞白血病（APL）和青少年白血病 骨髓单核细胞白血病（JMML）。 在APL中，全反式RA诱导完全 大多数患者病情缓解，但由于快速复发， RA抗性的发展和RA毒性的诱导。 的试剂 需要更有效和不导致耐药性。 有些孩子 JMML用13-cis-RA稳定，直到他们可以接受骨髓 移植在年龄较大，但更有效的代理人需要延长 更大比例的患者稳定。 该项目将开发 比RA更有效治疗APL的新型维甲酸， JMML。 这些新药将来自一类独特的类维生素A， 由UAB的研究者和合作研究者开发， 应用程序. 来自该类别的两种UAB 8异构体显示出更多的 在APL模型中比RA有效，在JMML模型中与RA一样有效， 然而，它们的毒性较低，并表现出更有利的药理学作用， profile. 他们将首先更全面地探索UAB 8的活动， 我们将优化UAB类维生素A的结构，为临床提供最佳的 APL和JMML治疗的候选者。 为了实现这一目标， 有类维生素A研究背景的科学家聚集在一起， 包括药物化学家，临床肿瘤学家，生物化学家， 药理学家 该小组将采用基础广泛的方法，包括： 合成; B）核受体结合/反式激活试验; c）体外 测定（APL细胞中分化和/或凋亡的诱导，和 抑制鼠和人JMML集落形成; d）药理学 小鼠体内代谢自诱导的研究和e）体内 在JMML小鼠模型中进行评估。

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.