Enhancing the efficacy of nucleoside analogs

增强核苷类似物的功效

• 批准号: 7099557
• 负责人: ARNON LAVIE
• 金额: $ 23.91万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099557
• 关键词: NOD mouse; SCID mouse; alcohol phosphotransferase; antineoplastics; bone marrow; cell line; clinical research; cytosine arabinoside; deoxycytidine; disease /disorder model; drug delivery systems; drug metabolism; drug screening /evaluation; enzyme activity; enzyme therapy; human genetic material tag; human tissue; immunoconjugates; leukemia; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; nucleoside analog; phosphorylation; prodrugs; synthetic enzyme

DESCRIPTION (provided by applicant): Despite advances in treating hematological malignancies, most patients either do not achieve remission or relapse after an initial therapeutic response. Nucleoside analogues (NAs), including arabinosyl cytosine (ara-C), fludarabine, cladribine, pentostatin, and more recently gemcitabine, troxcitabine and arabinosyl guanine (ara-G), are among the most important therapeutic agents currently used to treat hematological malignancies. Their antitumor activity depends on conversion to active, phosphorylated metabolites by intracellular kinases. Deoxycytidine kinase (dCK) catalyzes the rate-limiting phosphorylation step for the activation of all of these prodrugs. This application seeks (1) to develop a therapeutic system for delivery of dCK to the intracellular compartment to overcome the rate limiting step in NA activation, and (2) to engineer enzymes with improved catalytic activity for this therapeutic system. We will use ara-C as the model chemotherapeutic dCK substrate for these studies and an anti-CD33 antibody as the tumor targeting ligand. CD33 antigen is expressed by myeloid leukemia blasts, but not hematopoietic stem cells or other tissues. We will test the application that this "conjugate therapy" will increase the intracellular form of ara-C (ara-C triphosphate) and enhance its chemotherapeutic effect both in vitro and in vivo. We will manipulate enzyme structure with the goal of increasing both the efficacy and the therapeutic index of combined treatment with nucleoside analogues. Several tumor targeting antibodies are already in clinical use to internalize an attached protein, drug, or radioisotope into tumor cells. The selective delivery of enzymes with increased kinase activity that is proposed here has the potential advantage of reduced toxicity compared with radioisotope and drug systems. The long-term goal of this project is to develop methods to translate this Selective Enhanced Enzyme Delivery System (SEEDS) to applications for multiple types of malignancies.

描述（由申请人提供）：尽管治疗血液系统恶性肿瘤的进展，大多数患者要么在初始治疗反应后无法缓解或复发。核苷类似物（NAS），包括阿拉伯蛋白酶基胞嘧啶（ARA-C），氟达拉滨，克拉德替替替替替替替肽，五替汀以及最近的吉西他滨，Troxcitabine和Arabinosyl鸟嘌呤（ARA-G），是目前用于治疗血液学恶化的最重要的治疗药物之一。它们的抗肿瘤活性取决于细胞内激酶向活性的磷酸化代谢产物的转化。脱氧胞苷激酶（DCK）催化所有这些前药的激活速率磷酸化步骤。该应用程序寻求（1）开发一种治疗系统，用于将DCK传递到细胞内室，以克服NA激活中的速率限制步骤，以及（2）对这种治疗系统的催化活性改善的酶。我们将使用ARA-C作为这些研究的模型化学治疗DCK底物，将抗CD33抗体作为靶向配体的抗CD33抗体。 CD33抗原由髓样白血病爆炸表达，而不是造血干细胞或其他组织。我们将测试这种“结合疗法”将增加ARA-C（ARA-C三磷酸）的细胞内形式，并在体外和体内增强其化学治疗效果。我们将操纵酶结构，以增加与核苷类似物联合治疗的疗效和治疗指数。几种靶向抗体已经在临床中用于将附着的蛋白质，药物或放射性同位素内化到肿瘤细胞中。与放射性同位素和药物系统相比，此处提出的具有增加的激酶活性的酶的选择性递送具有降低毒性的潜在优势。该项目的长期目标是开发将这种选择性增强的酶输送系统（种子）转换为多种类型恶性肿瘤的应用的方法。