Development of 8-chloro-adenosine therapy

核苷类似物在血液系统恶性肿瘤的治疗中发挥了关键作用。而当 第一个类似物是在50多年前使用的，在过去的五年里，有四个新的同类药物是FDA 被批准接受治疗。这些临床使用的类似物的一个共同特征是它们都是DNA 定向的；仅影响RNA的类似物还没有带到临床上。八号 氯腺苷(8-CI-ADO)是一种新颖而独特的核苷类似物，在同类药物中首次在 诊所。首先，与其他临床使用的类似物不同，这种药物含有一种糖类。第二，8-CI- 腺苷被腺苷激酶磷酸化，腺苷激酶在癌细胞中具有很高的比活性，如 与激活当前使用的类似物的脱氧胞苷酸激酶相反。第三，8-CI-的三磷酸- ADO，8-CI-ATP被掺入到RNA中，对DNA合成没有任何影响。第四，8-CI-ATP也是 掺入到转录本的聚(A)尾部，导致抑制多聚腺苷和mRNA的合成。AS 作为对信使核糖核酸合成作用的结果，短命超越物的枯竭。第五, 生化研究和分子模拟数据表明，8-CI-ADP是底物，8-CI-ADP是底物。 ATP是线粒体ATP合成酶的抑制物，线粒体是氧化磷酸化的顶端酶 导致细胞生物能量耗尽的途径。总而言之，这些功能使该模拟成为 是班上第一名。基于这一背景，我们推测8-氯-腺苷将产生新的药效学。 对不生长或迟钝的恶性细胞的反应。8-CI-ADO的独特性得到同行的认可 在这一领域，我们获得了NCI的两个RAID奖，FDA的IND奖，以及GMP材料 我们对慢性淋巴细胞性白血病患者的I期临床研究。为了实现我们的总体目标并检验我们的假设， 我们计划实现以下三个目标。首先，使用定义明确的生物标志物，评估药物动力学 8-CI-ADO在慢性淋巴细胞性白血病患者L/11期临床试验中的药效学。第二，制定 8-氯-腺苷与小分子基于机理的组合临床翻译的体外理论基础 抑制剂。第三，确定淋巴瘤细胞系的代谢、作用和细胞毒终点 转化为淋巴瘤的临床试验。 相关性(请参阅说明)： 该项目将测试一种新的试剂8-氯腺苷，用于慢性淋巴细胞白血病(CLL)和 淋巴瘤。这是同类药物中第一个进入临床的药物。此外，不同的战略将是 关于该制剂的最佳组合方法进行了调查。因此，这些调查的目的是 提高慢性淋巴细胞性白血病和淋巴瘤的治愈率。

Nucleoside analogues have a played pivotal role in the treatment of hematological malignancies. While the first analogue was used more than 50 years ago, during the last five years, four new congeners were FDA approved for therapy. A common feature among these clinically used analogues is that they are all DNA directed; analogues that are exclusively affecting RNA have not been brought to the clinic. 8- chloroadenosine (8-CI-Ado) is a novel and unique nucleoside analogue that is first in its class to be tested in the clinic. First, in contrast to other clinically used analogues, this agent has a nbose sugar. Second, 8-CI- Ado is phosphorylated by adenosine kinase which is present in high specific activity in cancer cells as opposed to deoxycytidine kinase which activates currently used analogues. Third, the triphosphate of 8-CI- Ado, 8-CI-ATP is incorporated into RNA without any effect on DNA synthesis. Fourth, 8-CI-ATP is also incorporated into poly(A) tail of transcripts resulting in inhibition of polyadenylafion and mRNA synthesis. As a consequence of the actions on mRNA synthesis, there is a depletion of short-lived transcnpts. Fifth, biochemical studies and molecular modeling data have suggested that 8-CI-ADP is a substrate and 8-CI- ATP is an inhibitor for mitochondrial ATP synthase, the apical enzyme of the oxidative phosphorylation pathway which results in a depletion of cellular bioenergy. Collectively these features make this analogue a first in its class. Based on this background, we hypothesize that 8-Cl-Ado will elicit novel pharmacodynamic responses to non-growing or indolent malignant cells. The uniqueness of 8-CI-Ado was recognized by peers in this field as we obtained two RAID awards from NCI, an IND from the FDA, and GMP material to conduct our phase I clinical investigation in patients with CLL. To achieve our overall goal and to test our hypothesis, we plan to pursue the following three aims. First, using well-defined biomarkers, evaluate pharmacokinetics and pharmacodynamics of 8-CI-Ado during phase l/ll clinical trial in patients with CLL. Second, formulate in vitro rationales for clinical translation of mechanism-based combinations of 8-Cl-Ado with small molecule inhibitors. Third, determine metabolism, actions, and cytotoxic endpoints in lymphoma cell lines that will be translated to a clinical trial in lymphoma. RELEVANCE (See instmctions): This Project will test a new agent 8-chloro-adenosine, in chronic lymphocytic leukemia (CLL) and lymphoma. This is a first in its kind of agent to move to clinic. Additionally, different strategies will be investigated regarding best combination approaches for this agent. Hence these investigations are aimed at improving the cure rate of CLL and lymphoma.