Project 2: Optimizing Redox Modulation as a Therapeutic Strategy for NHL

项目二： 三萜类化合物是新的亲电化合物，我们已经表明诱导细胞凋亡， 套细胞淋巴瘤（MCL）和弥漫性大细胞淋巴瘤（DLCL）。事实上，我们的出版和初步 研究表明，这些化合物通过增加细胞毒性的产生， 活性氧（ROS），并降低这种关键的抗氧化防御机制的活性 硫氧还蛋白（Trx）和线粒体！蛋白酶，Lon和ClpXP。这表明一种新的治疗方法 基于调节淋巴瘤细胞氧化还原状态的淋巴瘤治疗策略。此外，我们建议 机制表明，其他氧化还原活性剂，如蛋白体抑制剂和组蛋白去乙酰化酶， 抑制剂是与三萜类化合物联合收割机的基本试剂。该提案的具体目标是 旨在提供支持临床评价所需的基本临床前数据， 最佳三萜类化合物和其他氧化还原活性剂组合用于DLCL和MCL患者。 具体而言，在具体目标1中，我们将验证我们提出的三萜类化合物的活性机制， 体外优化三萜类药物组合。这些组合将进一步优化， 使用DLCL在体内验证的ROS生成、Trx和线粒体蛋白酶的生物学靶点， Specific Aim 2中的MCL/SCID异种移植模型。我们预计，从这些具体目标中获得的数据 将提出一个最佳的三萜类化合物的组合，和顺序的药物输送研究的背景下， 具体目标3中提出的I/II期试验。这项试验的一个关键组成部分将是 实验室研究，据此我们建议确定该药物组合对ROS、Trx 和线粒体蛋白酶活性。进一步预计， 从这些研究中了解到的信息将支持我们的长期目标，即了解 NHL中的亲电化合物家族，其还包括孤雌菊内酯、葫芦蛋白和 acivicins，更重要的是如何最好地利用淋巴瘤的氧化还原状态，以产生新的， 治疗NHL的有效方法。

Project 2: The triterpenoids are novel electrophilic compounds that we have shown induce apoptotic cell death in mantle cell lymphoma (MCL) and diffuse large cell lymphoma (DLCL). Indeed our published and preliminary studies suggest that these compounds manifest their cytotoxic effects by both increasing the generation of reactive oxygen species (ROS), and decreasing the activity of such critical anti-oxidant defense mechanisms as thioredoxin (Trx) and the mitochondria! proteases, Lon and CIpXP. This suggests a novel therapeutic strategy for lymphoma based on modulating the lymphoma cell redox state. In addition, our proposed mechanism suggests that other redox active agents, such as proteosome inhibitors and histone deacetylase inhibitors, are rationale agents to combine with the triterpenoids. The Specific Aims of this proposal have been developed to provide the essential pre-clinical data needed to support the clinical evaluation of the optimal triterpenoid and other redox active agent combinations for patients with DLCL and MCL. Specifically, in Specific Aim 1, we will validate our proposed mechanism of activity of the triterpenoids so to optimize triterpenoid drug combinations in vitro. These combinations will be further optimized and the biological targets of ROS generation, Trx and mitochondrial proteases validated in vivo using DLCL and MCL/SCID xenograft models in Specific Aim 2. We anticipate that the data derived from these Specific Aims will suggest an optimal triterpenoid combination, and sequence of drug delivery to be studied in the context of a phase l/ll trial as proposed in Specific Aim 3. A critical component of this trial will be the correlative laboratory studies whereby we propose to determine the in vivo effects of this drug combination on ROS, Trx and mitochondrial protease activity in patients with lymphoma. It is further anticipated that the lessons learned from these studies will support our long term goals which are to understand the clinical potential of the family of electrophilic compounds in NHL, which also includes the parthenolides, cucurmin, and the acivicins, and more importantly how best to exploit the redox state of lymphoma to generate new and effective approaches for the treatment of patients with NHL.