Nucleoside Analogs as Anticancer Compounds

该提案的总体目标是开发用于治疗癌症的脱氧核苷类似物。 这包括对新型核苷类似物的作用机制和耐药性的研究，以及 探索新的策略以有效地使用胡桃苷类似物对抗癌症。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构型抗癌药物， 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的生物化学决定簇，其允许这种磷酸化程度低的类似物在 存在高得多浓度的天然存在的胞苷（Cyd）核苷酸， 了解L-OddC如何发挥作用，并探索更有效地使用它的新策略。的 L-OddC与吉西他滨（dFdC）（一种D-构型脱氧胞苷类似物）一起结构显示于 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.探讨缺氧的作用： a.在调节磷酸甘油酸激酶（PGK），这是负责磷酸化的L- OddCDP到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方面的影响： 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。它应该会产生新的信息， 了解L-OddC作用的生化决定因素，酶的生物化学 L-OddC用于治疗实体瘤的研究和可能的新用途。

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 nucteoside 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 onthe: 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.