Radionuclide-based Molecular Imaging of the DNA Repair Protein AGT

DNA 修复蛋白 AGT 的放射性核素分子成像

• 批准号: 7659042
• 负责人: GANESAN VAIDYANATHAN
• 金额: $ 23.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659042
• 关键词: Active Sites; Adverse effects; Affect; Alkylating Agents; Alkylating Antineoplastic Agents; Benzene; Binding; Brain Neoplasms; Cell Line; Cell Nucleus; Clinical; Coupled; Cysteine; DNA; DNA lesion; DNA repair protein; Deoxyguanosine; Development; Drug resistance; Economics; Effectiveness; Goals; Guanine; Image; Imaging Techniques; In Vitro; Individual; Iodine; Label; Laboratories; Lesion; Malignant Neoplasms; Malignant neoplasm of brain; Methods; Modeling; Monitor; Nuclear; Nude Mice; O(6)-Methylguanine-DNA Methyltransferase; O(6)-benzylguanine; Outcome; Patients; Play; Positioning Attribute; Positron-Emission Tomography; Process; Proteins; Radioisotopes; Radiolabeled; Role; Survival Rate; Techniques; Therapeutic; Time; Tracer; Triage; Tumor Cell Nuclei; Work; Xenograft Model; Xenograft procedure; alkyl group; alternative treatment; base; cancer therapy; cancer type; chemotherapy; design; functional group; in vivo; molecular imaging; mouse model; neoplastic cell; protein aminoacid sequence; public health relevance; radiotracer; repaired; single photon emission computed tomography; stem; suicidal; tool; tumor; tumor growth; tumor xenograft; uptake

DESCRIPTION (provided by applicant): Alkylator chemotherapy plays a significant role in the treatment of brain tumors and other malignancies. However, its effectiveness is all too often limited by drug resistance, which leads to lethal growth of tumors despite further rounds of alkylator chemotherapy. Drug resistance to alkylator chemotherapy is primarily due to the repair of induced O6-alkylguanine DNA lesions by the protein alkylguanine-DNA alkyltransferase (AGT). There is a well-established inverse correlation between tumor AGT content and therapeutic outcome; generally, survival rates are higher when the AGT content of tumor is below a threshold. We hypothesize that it should be possible to decide whether to administer alkylator chemotherapy in individual patients based on noninvasive imaging of tumor AGT levels prior to therapy. The goal of this work is to develop radiolabeled agents that will allow assessment of AGT levels using SPECT or PET imaging. We propose to synthesize radioiodinated derivatives of O6- benzylguanine (BG), a potent AGT inactivating agent, coupled to nuclear localizing peptide sequences (NLS) to enhance delivery of the labeled substrate to the cell nucleus where AGT is predominantly present. These labeled agents will be evaluated in vitro using pure AGT and AGT-expressing cell lines and in vivo using xenograft models. The specific aims are: 1. To synthesize benzylguanine derivatives and their NLS conjugates. 2. To evaluate the radiolabeled benzylguanines and their NLS conjugates for binding to pure AGT and in tumor cells in vitro. 3. To evaluate AGT-specific radiolabeled agents developed in athymic mouse xenograft models. A successful agent for the molecular imaging of AGT could be an important tool that can be used to avoid unnecessary chemotherapy; in addition to the economic benefits, it can spare patients from the major side effects of alkylator chemotherapy, and allow them to be triaged earlier to alternative treatments. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop radiolabeled tracers that can be utilized as molecular imaging agents for the noninvasive assessment of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) in brain cancers and other tumors. AGT is primarily responsible for the drug resistance that frequently compromises the effectiveness of alkylator-based chemotherapy of many cancers. Because drug resistance is a major road block in the cancer treatment process, the availability of a molecular imaging technique to quantify AGT will have a significant clinical impact. With such a technique, chemotherapy can be personalized because it should be possible to predict which patients will benefit from chemotherapy and which will not. This will help avoid treating patients for whom alkylator chemotherapy will be largely ineffective, sparing them of unwarranted side effects and expense, and providing an earlier rationale for seeking alternative treatments that might be more successful, given their AGT status.

描述（申请人提供）：烷基化化疗在脑肿瘤和其他恶性肿瘤的治疗中起着重要作用。然而，它的有效性往往受到耐药性的限制，这导致肿瘤的致命生长，尽管再进行几轮烷基化化疗。对烷基化化疗的耐药主要是由于烷基鸟嘌呤-DNA烷基转移酶（AGT）蛋白修复诱导的o6 -烷基鸟嘌呤DNA损伤。肿瘤AGT含量与治疗结果之间存在明显的负相关；一般情况下，肿瘤中AGT含量低于阈值时，生存率较高。我们假设，应该有可能根据治疗前肿瘤AGT水平的无创成像来决定是否对个别患者进行烷基化化疗。这项工作的目标是开发放射性标记剂，将允许使用SPECT或PET成像评估AGT水平。我们建议合成O6-苄基鸟嘌呤（BG）的放射性碘化衍生物，这是一种有效的AGT灭活剂，与核定位肽序列（NLS）偶联，以增强标记的底物向AGT主要存在的细胞核的传递。这些标记的药物将在体外使用纯AGT和表达AGT的细胞系进行评估，在体内使用异种移植模型进行评估。具体目标是：1。合成苯鸟嘌呤衍生物及其NLS缀合物。2. 目的评价放射标记的苯鸟嘌呤及其NLS偶联物与AGT的体外结合及与肿瘤细胞的体外结合。3. 目的：评价agt特异性放射标记剂在胸腺小鼠异种移植模型中的应用。一种成功的AGT分子成像药物可以成为避免不必要的化疗的重要工具；除了经济效益外，它还可以使患者免受烷基化化疗的主要副作用，并使他们能够更早地接受替代治疗。公共卫生相关性：该项目的目标是开发放射性标记示踪剂，可作为分子显像剂，用于无创评估脑癌和其他肿瘤中的DNA修复蛋白烷基鸟嘌呤-DNA烷基转移酶（AGT）。AGT是导致耐药的主要原因，这种耐药经常影响许多癌症基于烷基化剂的化疗的有效性。由于耐药性是癌症治疗过程中的主要障碍，因此量化AGT的分子成像技术的可用性将具有重大的临床影响。有了这种技术，化疗可以个性化，因为可以预测哪些病人会从化疗中受益，哪些不会。这将有助于避免治疗烷基化化疗在很大程度上无效的患者，使他们免受不必要的副作用和费用，并为寻求可能更成功的替代治疗提供更早的理由，考虑到他们的AGT状态。