NOVEL RETINOIDS FOR LEUKEMIA THERAPY

描述：维甲酸(RA)是主要的临床有用的治疗方法。 两种白血病，急性早幼粒细胞白血病和青少年 粒单核细胞白血病(JMML)。在急性早幼粒细胞白血病中，全反式RA诱导完全 大多数患者病情缓解，但由于复发迅速，复发很常见 RA抗性的发展和RA毒性的诱导。属于以下对象的代理 需要更有效且不会导致阻力的措施。一些儿童患有 JMML用13-顺式维甲酸稳定，直到他们可以接受骨髓 移植的年龄较大，但需要更有效的药物来推广 稳定到更大比例的患者。这个项目将会发展 治疗急性早幼粒细胞白血病和急性早幼粒细胞白血病的新维甲酸类药物 JMML。这些新药将从一种独特的维甲酸类化合物中提取 是由UAB的调查员和联合调查员开发的 申请。这一类的两个UAB8异构体被证明是更多 在APL模型中比RA有效并且在JMML模型中与RA一样有效， 然而，它们的毒性较小，并显示出更有利的药理作用 侧写。他们将首先更全面地探索UAB8的活动，然后 我们将优化UAB维甲酸的结构，为临床提供最好的 APL和JMML治疗的候选对象。为了实现这一目标，一个由 有维甲酸研究背景的科学家已经聚集在一起， 包括药物化学家、临床肿瘤学家、生物化学家， 药剂学家。该团队将使用基础广泛的方法，包括) 合成；b)核受体结合/反式激活试验；c)体外 检测(诱导APL细胞分化和/或凋亡，以及 抑制小鼠和人JMML集落形成；d)药理学 小鼠自诱导代谢和体内代谢的研究 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.