Nucleoside Analogs as Anticancer Compounds

这项提议的总体目标是开发用于癌症治疗的脱氧核苷类似物。 这包括对新型核苷类似物的作用机制和抗药性的研究，以及对 探索使用核苷类似物有效抗癌的新策略。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构型抗癌药物 脱氧胞苷(DCyd)类似物，目前处于第三阶段临床试验。其目的将是研究 L-OddC的生化决定因素允许这种低磷酸化的类似物在体内充分激活 存在浓度高得多的自然产生的胞苷(Cyd)核苷酸和 了解L是如何发挥其作用的，以及探索一种新的战略，以更有效地利用它。这个 L-OddC与D-构型脱氧胞苷类似物吉西他滨(DFDC)的结构显示在 图1.具体目标如下： 1.探讨cMP/UMP激酶在L-OddcMP和dFdcMP磷酸化中的作用。 2.研究缺氧的作用： A.在调节负责L磷酸化的磷酸甘油酸激酶(PGK)中- OddCDP给L-OddCTP。 B.在L-OddC的细胞毒性中，L-OddCTP的形成和L-OddC的DNA掺入。 3.为了研究抗血管生成化合物沙利度胺对血管生成的影响： 1.L的抗肿瘤活性。 B.肿瘤组织中PGK和APE-1的表达。 拟议的研究是基于这个实验室的原始发现。它应该产生新的信息，用于 了解L-OddC作用的生化决定因素，酶的生物化学 研究了L-OddC治疗实体瘤的可能新用途。

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.