MICRO-PET IMAGING OF ALKYLGUANINE-DNA ALKYLTRANSFERASE (AGT)

烷基鸟嘌呤-DNA 烷基转移酶 (AGT) 的显微 PET 成像

• 批准号: 7358332
• 负责人: GANESAN VAIDYANATHAN
• 金额: $ 0.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7358332
• 关键词: MICRO; PET; IMAGING; ALKYLGUANINE; DNA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cytotoxic action of chemotherapeutic alkylating agents stems from the alkylation of DNA at the O6-position of DNA guanine residues. Subsequent to alkylation, a cascade of events takes place resulting in eventual DNA strand breaks. Drug resistance seen in alkylator chemotherapy of various cancers has been primarily attributed to the DNA repair protein Alkylguanine-DNA alkyltransferase (AGT). AGT transfers the guanine O6-alkyl group to a cysteine in its active site thereby repairing the DNA. This is a stoichiometric or suicidal process; once its cysteine-145 is alkylated, AGT undergoes degradation via ubiquitin pathway and new AGT can only be regenerated by de novo synthesis. A number of preclinical as well as retrospective and prospective clinical studies have demonstrated an inverse correlation between the tumor AGT content and the positive clinical outcome of alkylator chemotherapy. Also, tumor AGT content varies not only between different tumor types but also within a group of patients of same malignancy. Thus, a prior knowledge of the tumor AGT content can help oncologists to tailor chemotherapy on a patient-specific basis. Our goal is to develop radiolabeled agents with which it should be possible to quantify tumor AGT content in a noninvasive fashion by PET or SPECT imaging. O6-benzylguanine (BG) is a substrate for AGT and is undergoing clinical studies as an AGT modulator. We have developed a radioiodinated BG analogue namely, O6-3-[*I]iodobenzylguanine (IBG) which has shown to label AGT specifically. Recently this compound has been tagged with I-124. The goal of this work is to track this agent in a mouse xenograft model. We would like to determine whether tumors of a control group and of a group whose tumor AGT is depleted can be differentiated. The ultimate goal of our project is to develop radiolabeled agents with which it should be possible to quantify AGT by PET or SPECT imaging. Thus it is critical to demonstrate that it can be done in an animal model first. In addition, it is necessary to eatablish that it is possible to image animal models with DUMC microPET using I-124 tagged radiopharmaceuticals.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。化疗烷化剂的细胞毒作用源于DNA鸟嘌呤残基O6位的DNA烷基化。烷基化之后，会发生一系列事件，最终导致 DNA 链断裂。各种癌症的烷化剂化疗中出现的耐药性主要归因于 DNA 修复蛋白烷基鸟嘌呤-DNA 烷基转移酶 (AGT)。 AGT 将鸟嘌呤 O6-烷基转移至其活性位点的半胱氨酸，从而修复 DNA。这是一个化学计量或自杀过程；一旦其半胱氨酸145被烷基化，AGT就会通过泛素途径降解，新的AGT只能通过从头合成来再生。大量临床前以及回顾性和前瞻性临床研究表明，肿瘤AGT含量与烷化剂化疗的阳性临床结果之间呈负相关。此外，肿瘤 AGT 含量不仅在不同肿瘤类型之间存在差异，而且在同一恶性肿瘤患者组内也存在差异。因此，预先了解肿瘤 AGT 含量可以帮助肿瘤学家根据患者的具体情况制定化疗方案。我们的目标是开发放射性标记药物，通过 PET 或 SPECT 成像以无创方式量化肿瘤 AGT 含量。 O6-苄基鸟嘌呤 (BG) 是 AGT 的底物，作为 AGT 调节剂正在进行临床研究。我们开发了一种放射性碘标记的 BG 类似物，即 O6-3-[*I]碘苄基鸟嘌呤 (IBG)，它已被证明可以特异性标记 AGT。最近，该化合物已被标记为 I-124。这项工作的目标是在小鼠异种移植模型中追踪该药物。我们想确定是否可以区分对照组的肿瘤和肿瘤 AGT 耗尽的组的肿瘤。 我们项目的最终目标是开发放射性标记试剂，通过 PET 或 SPECT 成像可以量化 AGT。因此，首先证明它可以在动物模型中完成是至关重要的。此外，有必要确定可以使用 I-124 标记的放射性药物通过 DUMC microPET 对动物模型进行成像。