Nucleoside Analogs as Anticancer Compounds

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。这包括对新型核苷类似物的作用机制和耐药性的研究，以及利用核苷类似物有效抗癌的新策略的探索。我们的研究将集中在这个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存在的胞苷（Cyd）核苷酸存在下充分激活这种低磷酸化类似物，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。探讨CMP/UMP激酶在L-OddCMP和dFdCMP磷酸化中的作用。2. 研究缺氧在调节磷酸甘油酸激酶（PGK）中的作用，该激酶负责L- OddCDP磷酸化为L- oddctp。b.在L-OddC的细胞毒性中，L-OddCTP的形成和L-OddC并入DNA。3. 研究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Apurinic/apyrimidic核酸内切酶-1 （APE-1）的表达。提出的研究是基于本实验室的原始发现。它将为理解L-OddC作用的生化决定因素、所研究的酶的生物化学以及L-OddC在实体肿瘤治疗中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.