Nucleoside Analogs as Anticancer Compounds

作为抗癌化合物的核苷类似物

• 批准号: 7911052
• 负责人: YUNG-CHI CHENG
• 金额: $ 9.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911052
• 关键词: Biochemical; Biochemistry; Cytidine; Cytidylate kinase; DNA; Deoxycytidine; Development; Enzymes; Hypoxia; Laboratories; Malignant Neoplasms; Nucleotides; Phase III Clinical Trials; Phosphoglycerate Kinase; Phosphorylation; Resistance; Role; Solid Neoplasm; Structure; Thalidomide; Troxacitabine; analog; antiangiogenesis therapy; base; cancer therapy; cytotoxicity; endonuclease; gemcitabine; novel; novel strategies; nucleoside analog; tumor

DESCRIPTION (provided by applicant): The overall aim of this proposal is the development of deoxynucleoside analogs for the treatment of cancer. This includes studies on the mechanism of action and resistance of novel nucleoside analogs as well as the exploration of novel strategies to use nucleoside analogs effectively against cancer. Our studies will center on one compound discovered by this laboratory: Troxacitabine (L-OddC), a novel L-configuration anticancer deoxycytidine (dCyd) analog that is currently under phase III clinical trial. The aim will be to study the biochemical determinants of L-OddC that allow sufficient activation of this poorly phosphorylated analog in the presence of much higher concentrations of naturally occurring cytidine (Cyd) nucleotides and to understand how L-OddC exerts its action, as well as explore a novel strategy to use it more effectively. The structure of L-OddC together with Gemcitabine (dFdC), a D-configuration deoxycytidine analog, is shown in Figure 1. Specific Aims are listed as follows: 1. To examine the role of CMP/UMP kinase in the phosphorylation of L-OddCMP and dFdCMP. 2. To examine the role of Hypoxia: a. in regulating phosphoglycerate kinase (PGK), which is responsible for the phosphorylation of L- OddCDP to L-OddCTP. b. in cytotoxicity of L-OddC, the formation of L-OddCTP and incorporation of L-OddC into DNA. 3. To examine the impact of the antiangiogenesis compound, thalidomide on the: a. Antitumor activity of L-OddC. b. Expression of PGK and Apurinic/apyrimidic endonuclease -1 (APE-1) in tumor. The proposed studies are based on original findings in this laboratory. It should yield novel information for understanding the biochemical determinants of the action of L-OddC, the biochemistry of the enzymes studied and possible novel use of L-OddC for the treatment of solid tumor.

描述（由申请人提供）：本提案的总体目标是开发用于治疗癌症的脱氧核苷类似物。这包括研究新型核苷类似物的作用机制和耐药性，以及探索使用核苷类似物有效对抗癌症的新策略。我们的研究将集中在本实验室发现的一种化合物：曲沙他滨（L-OddC），一种新型L-构型抗癌脱氧胞苷（dCyd）类似物，目前正在进行III期临床试验。目的是研究L-OddC的生化决定因素，这些决定因素允许在更高浓度的天然胞苷（Cyd）核苷酸存在下充分激活这种磷酸化程度很差的类似物，并了解L-OddC如何发挥其作用，以及探索一种更有效地使用它的新策略。L-OddC与吉西他滨（dFdC）（一种D-构型脱氧胞苷类似物）的结构见图1。具体目标如下：1.研究CMP/UMP激酶在L-OddCMP和dFdCMP磷酸化中的作用。2.要检查缺氧的作用：a。调节磷酸甘油酸激酶（PGK），其负责L-OddCDP磷酸化为L-OddCTP。B. L-OddC的细胞毒性、L-OddCTP的形成和L-OddC掺入DNA中。3.为了检查抗血管生成化合物沙利度胺对以下的影响：a. L-OddC的抗肿瘤活性。B. PGK和APE-1在肿瘤中的表达拟议的研究是基于该实验室的原始发现。它应该产生新的信息，了解L-OddC的行动，生物化学的酶的研究和可能的新用途的L-OddC治疗实体瘤的生化决定因素。