In Vivo EPR Imaging of Redox Status and Thiols in Tumor

肿瘤中氧化还原状态和硫醇的体内 EPR 成像

• 批准号: 7030987
• 负责人: PERIANNAN KUPPUSAMY
• 金额: $ 29.93万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030987
• 关键词: antineoplastics; athymic mouse; carboplatin; cisplatin; electron spin resonance spectroscopy; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; ovary neoplasms; oxidation reduction reaction; paclitaxel; platinum; technology /technique development; thiols; xenotransplantation

DESCRIPTION (provided by applicant): Ovarian Cancer is the fifth leading cause of death among women in the United States. Early stages of this disease are usually asymptomatic with high malignant potential. Due to lack of adequate diagnostic techniques, the disease is usually detected at late stages. Surgery is used for debulking followed by chemotherapy as a supplemental treatment modality. Platinum-based complexes (for example, cisplatin, carboplatin) in combination with natural products (e.g. paclitaxel, docetaxel) are the primary chemotherapeutic agents used in the treatment of ovarian cancer. However, a major limitation to the success of the platinum-based chemotherapeutic regimen is the frequent development of drug resistance in the recurrent tumor. Evidences suggest that increased cellular thiol levels are associated with the reduced sensitivity of tumor cells to cisplatin. Therefore, a reliable and noninvasive method to determine the thiol level in the tumor should be a useful adjunct for the clinical oncology, pharmacology and chronotherapy of ovarian cancer. The objective of this proposal is to develop and apply electron paramagnetic resonance (EPR) spectroscopy and imaging techniques to measure tumor redox status, including thiol levels, in vivo. The EPR technique has the unique advantage of direct and noninvasive detection of overall redox as well as thiol redox in tissues. In addition, reliable and accurate in vitro measurements can be performed in cell suspension and biopsy tissues with ease of preparation and minimum processing. Preliminary data on in vitro cellular systems and in vivo murine tumor models show that the thiol levels can be measured and imaged utilizing EPR spectroscopy. The specific aims are: 1. Development of an in vitro EPR technique to perform measurement of intracellular thiols in human ovarian cancer cells; 2. Development of in vivo EPR techniques to perform non-invasive imaging of redox status and thiols of normal tissue and tumor in mice; 3. Monitoring thiol levels in ovarian cancer cells before, during and after treatment with platinum antitumor drugs and taxanes; 4. In vivo measurement and imaging of thiols in human ovarian cancer cells grown as solid tumor xenografts in athymic nude mice. The results will enable a better understanding of the development of drug resistance in ovarian cancer and offer efficient diagnosis for effective treatment of ovarian cancer patients.

描述（由申请人提供）：卵巢癌是美国妇女死亡的第五大原因。这种疾病的早期阶段通常是无症状的，具有高度恶性潜能。由于缺乏足够的诊断技术，这种疾病通常在晚期才被发现。手术用于减积，然后化疗作为补充治疗方式。铂基复合物（例如顺铂、卡铂）与天然产物（例如紫杉醇、多西他赛）的组合是用于治疗卵巢癌的主要化学治疗剂。然而，基于铂的化疗方案成功的主要限制是复发性肿瘤中频繁出现耐药性。有证据表明，增加的细胞巯基水平与肿瘤细胞对顺铂的敏感性降低有关。因此，一个可靠的和非侵入性的方法来确定肿瘤中的巯基水平，将是一个有用的辅助临床肿瘤学，药理学和卵巢癌的时间治疗。本提案的目的是开发和应用电子顺磁共振（EPR）光谱和成像技术来测量肿瘤的氧化还原状态，包括硫醇水平，在体内。EPR技术具有直接、无创检测组织中总氧化还原和巯基氧化还原的独特优势。此外，可靠和准确的体外测量可以在细胞悬液和活检组织中进行，易于制备和最小化处理。体外细胞系统和体内小鼠肿瘤模型的初步数据表明，可以利用EPR光谱法测量和成像硫醇水平。具体目标是：1.建立了一种体外EPR技术，用于检测人卵巢癌细胞内巯基的含量; 2.开发体内EPR技术，对小鼠正常组织和肿瘤的氧化还原状态和巯基进行无创成像; 3.监测铂类抗肿瘤药物和紫杉烷类药物治疗前、治疗中和治疗后卵巢癌细胞中巯基水平; 4.在无胸腺裸小鼠中作为实体瘤异种移植物生长的人卵巢癌细胞中硫醇的体内测量和成像。这些结果将使我们能够更好地了解卵巢癌耐药的发展，并为卵巢癌患者的有效治疗提供有效的诊断。