Nucleoside Analogs as Anticancer Compounds

描述(申请人提供)：这项提案的总体目标是开发用于癌症治疗的脱氧核苷类似物。这包括研究新型核苷类似物的作用机制和抗药性，以及探索利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)，一种新型的L构型抗癌脱氧胞苷(DCyd)类似物，目前正在进行第三阶段临床试验。其目的将是研究L-OddC的生化决定因素，使这种低磷酸化的类似物在浓度高得多的天然胞苷(Cyd)核苷酸存在下被充分激活，并了解L-OddC是如何发挥作用的，以及探索更有效地使用它的新策略。L-OddC和D-构型脱氧胞苷类似物吉西他滨(DFDC)的结构如图1所示。具体目标如下：1.研究Cp/UMP激酶在L-OdCp和dFdCp磷酸化中的作用。2.研究缺氧对磷酸甘油酸激酶的调节作用，该蛋白负责L-OddCDP向L-OddCTP的磷酸化。B.在L-OddC的细胞毒性中，L-OddCTP的形成和L-OddC的DNA掺入。3.检测抗血管生成化合物沙利度胺对L-OddC抗肿瘤活性的影响。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。这将为理解L-奇数C作用的生化决定因素、所研究的酶的生物化学以及L-奇数C治疗实体瘤的可能的新用途提供新的信息。

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.