Nucleoside Analogs as Anticancer Compounds

描述：总体目标是开发脱氧核苷类似物， 治疗癌症患者。这包括对细胞凋亡机制的研究， 行动和阻力，以及探索新的战略，以发展 具有独特性质的新型核苷类似物。在这个应用程序中，我们将 继续专注于研究一种新的抗癌作用， L-脱氧核苷类似物，L（-）二氧戊环胞苷（L（-）OddC或BCH 4664） 目前正在进行II期临床试验 问题研究根据所取得的进展，具体目标如下：研究 AP内切酶（APE/ref-I）的作用，它被确定为是关键的 在从其3 '末端DNA中去除L（-）OddCMP的活性 L（-）OddC的细胞毒作用。(1)研究独特突变的影响， 可以改变AP核酸内切酶活性或其氧化还原调节活性， 从其3 ′-末端DNA中去除L（-）OddCMP的切除活性。 (2)研究APE/ref-I（有或没有独特突变）对 L（-）OddC在细胞中的作用。 (3)研究沙利度胺对L（-）OddC作用的影响，重点是 APE/ref-i表达。.研究CMP/UMP激酶在细胞凋亡中的功能作用。 L（-）OddCMP或dCMP磷酸化为它们的二磷酸核苷酸形式。 (1)检查改变细胞中CMP/UMP激酶蛋白表达的影响 对dCyd或L（-）OddC代谢的影响。(2)检查可能的更改 CMP/UMP激酶蛋白通过翻译后修饰状态，或 蛋白质相互作用促进L（-）OddCMP或dCMP磷酸化。（三） 检查是否存在尚未鉴定的dCMP激酶， 及其与dCMP、CMP、UMP、L（-）OddCMP、AraCMP和dFdCydMP的相互作用。的 拟议的研究是基于一些新的观察期间， 融资期。它不仅应该提供行动方面的信息， 所有脱氧胞苷类似物及其与其他类别的潜在相互作用 抗癌化合物，但也有一些基本知识， 核苷酸代谢和DNA修复的生物化学。

DESCRIPTION: The overall aim is to develop deoxynucleoside analogs for the treatment of patients with cancer. This includes the study of mechanism of action and resistance as well as the exploration of novel strategies to develop new nucleoside analogs with unique properties. In this application, we will continue to focus on the study of the anticancer action of a novel L-deoxynucleoside analog, L(-)dioxolane cytidine (L(-)OddC or BCH 4664) discovered in this laboratory and currently undergoing Phase II clinical studies. Based on the progress made, the Specific Aims are as follows: A. Study the role of AP endonuclease (APE/ref-I), which was identified to be the key activity in the removal of L(-)OddCMP from its 3'terminated DNA for the cytotoxic action of L(-)OddC. (1) Study the impact of unique mutations which could alter AP endonuclease activity or its redox regulatory activity, on its excision activity for the removal of L(-)OddCMP from its 3' -terminated DNA. (2) Study the impact of APE/ref-I, with or without unique mutations, on the action of L(-)OddC in cells. (3) Study the impact of thalidomide on the action of L(-)OddC with a focus on APE/ref-i expression. . Examine the functional role of CMP/UMP kinase for the phosphorylation of L(-)OddCMP or dCMP to their diphosphate nucleotide forms. (1) Examine the impact of altering CMP/UMP kinase protein expression in cells on dCyd or L(-)OddC metabolism. (2) Examine the possible alteration of the state of CMP/UMP kinase protein through post-translational modification or protein interaction in facilitating L(-)OddCMP or dCMP phosphorylation. (3) Examine the possible presence of dCMP kinase, which has not been identified, and its interaction with dCMP, CMP, UMP, L(-)OddCMP, AraCMP and dFdCydMP. The proposed study is based on some of the novel observations made during this funding period. It should provide information not only in terms of the action of all deoxycytidine analogs and their potential interaction with other classes of anticancer compounds, but also some basic knowledge regarding the biochemistry of nucleotide metabolism and DNA repair.