Thymidylate Synthase and Fluorodeoxyuridine Resistance

胸苷酸合酶和氟脱氧尿苷抗性

基本信息

批准号：
8267708
负责人：
FRANKLIN G. BERGER
金额：
$ 17.89万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-03-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267708
关键词：
Affinity Anabolism Animal Model Antimetabolites Antioxidants Binding Biology Cell Death Cell Line Cell Nucleus Cell Proliferation Cell Survival Chemotherapy-Oncologic Procedure Clinical Clinical Management DNA Damage DNA Repair DNA biosynthesis Disease Drug Delivery Systems Enzymes Equilibrium Floxuridine Fluorouracil Genome Goals Health Hydrogen Peroxide Knowledge Laboratories Lead Ligands Locales Measurement Mediating Methylation Mind Nuclear Outcome Pharmaceutical Preparations Post-Translational Protein Processing Reaction Reactive Oxygen Species Regulation Research Resistance Role Superoxides Testing Therapeutic Agents Thymidylate Synthase Thymidylate Synthase Inhibitor Time Toxic effect attenuation cancer therapy chemotherapy cytotoxicity enzyme structure fluoropyrimidine inhibitor/antagonist insight neoplastic novel polypeptide programs response tumor

项目摘要

DESCRIPTION (provided by applicant): Thymidylate synthase (TS) catalyzes the reductive methylation of dUMP to dTMP, a reaction that is essential for the de novo biosynthesis of dTTP for DNA replication and cell proliferation. Inhibitors of TS, such as the fluoropyrimidine antimetabolite 5-fluorouracil, have been important in the chemotherapy of cancer for quite some time, and remain a mainstay in the clinical management of neoplastic disease. A large body of research on TS and its inhibitors has led to detailed knowledge of the enzyme's structure (which governs its affinity for inhibitory ligands) and synthesis (which controls its intracellular concentrations). Recent studies by our group have identified new aspects of TS biology that will be important to further advances in the use of TS inhibitors for cancer treatment. The research program we propose in this application is a comprehensive one that focuses around several novel issues, including: the contribution of reactive oxygen species to the toxicity of TS inhibitors (AIM 1); post-translational modification of TS and regulation of its intracellular locale (AIM 2); and the function of nuclear TS in DNA repair and attenuation of genome damage (AIM 3). We suggest that response to TS inhibitors drugs depends upon the balance between ROS-dependent cell death and DNA repair-dependent cell survival. In all, this application proposes studies of newly recognized features of TS that should lead to novel insights into the role of this important drug target in cancer therapy. PUBLIC HEALTH RELEVANCE: Thymidylate synthase (TS) has been an important target for anticancer chemotherapy for decades. The goal of the proposed project is to test the effects of modulating the levels of reactive oxygen species (ROS) on tumor response to TS inhibitors and examine the ability of FUra to potentiate the cytotoxicity of different classes of anti-neoplastic agents. The results of these studies will be valuable in developing new and novel therapies in combination with TS inhibitors that might synergize to enhance their anti-tumor efficacy.

描述（由申请人提供）：胸苷酸合酶（TS）催化 dUMP 还原甲基化为 dTMP，该反应对于用于 DNA 复制和细胞增殖的 dTTP 从头生物合成至关重要。 TS 抑制剂，例如氟嘧啶抗代谢物 5-氟尿嘧啶，在相当长一段时间内在癌症化疗中发挥着重要作用，并且仍然是肿瘤疾病临床治疗的中流砥柱。对 TS 及其抑制剂的大量研究使人们对酶的结构（控制其对抑制性配体的亲和力）和合成（控制其细胞内浓度）有了详细的了解。我们小组最近的研究发现了 TS 生物学的新方面，这对于进一步推进 TS 抑制剂在癌症治疗中的应用非常重要。我们在本申请中提出的研究计划是一项综合性研究计划，重点围绕几个新问题，包括：活性氧对 TS 抑制剂毒性的贡献（AIM 1）； TS 的翻译后修饰及其细胞内区域的调节 (AIM 2)；以及核 TS 在 DNA 修复和基因组损伤减弱中的功能 (AIM 3)。我们认为，对 TS 抑制剂药物的反应取决于 ROS 依赖性细胞死亡和 DNA 修复依赖性细胞存活之间的平衡。总之，该申请提出了对新认识的 TS 特征的研究，这应该会对这一重要药物靶标在癌症治疗中的作用产生新的见解。公共健康相关性：几十年来，胸苷酸合酶 (TS) 一直是抗癌化疗的重要靶点。该项目的目标是测试调节活性氧 (ROS) 水平对肿瘤对 TS 抑制剂反应的影响，并检查 FUra 增强不同类别抗肿瘤药物细胞毒性的能力。这些研究的结果对于开发与 TS 抑制剂联合的新疗法非常有价值，这些疗法可能协同增强其抗肿瘤功效。