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: 6774504
• 负责人: PERIANNAN KUPPUSAMY
• 金额: $ 30.65万
• 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/6774504
• 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）：卵巢癌是美国妇女中第五大死亡原因。这种疾病的早期阶段通常是无症状的，具有高恶性潜力。由于缺乏足够的诊断技术，通常在晚期发现该疾病。手术用于脱毛，然后进行化学疗法作为补充治疗方式。铂基络合物（例如，顺铂，卡铂）与天然产物（例如紫杉醇，多西他赛）结合使用是用于治疗卵巢癌的主要化学治疗剂。但是，基于铂的化学治疗方案成功的主要局限性是复发性肿瘤中耐药性的频繁发展。证据表明，升高的细胞硫醇水平与肿瘤细胞对顺铂的敏感性降低有关。因此，确定肿瘤中硫醇水平的可靠且无创的方法应该是卵巢癌的临床肿瘤学，药理学和年级疗法的有用辅助方法。该提案的目的是在体内开发和应用电子顺磁共振（EPR）光谱和成像技术，以测量包括硫醇水平在内的肿瘤氧化还原状态。 EPR技术具有直接和非侵入性检测整体氧化还原以及组织中硫醇氧化还原的独特优势。另外，可以在细胞悬浮液和活检组织中进行可靠和准确的体外测量，并易于制备和最小的加工。关于体外细胞系统和体内鼠肿瘤模型的初步数据表明，可以通过EPR光谱法测量并成像硫醇水平。具体目的是：1。开发一种体外EPR技术，以测量人类卵巢癌细胞中细胞内硫醇的测量； 2。开发体内EPR技术以对小鼠正常组织和肿瘤的氧化还原状态和硫醇进行非侵入性成像； 3。在用铂抗肿瘤药物和紫杉烷治疗前，期间和治疗后，监测硫代癌细胞中的硫醇水平； 4。在人卵巢癌细胞中硫醇的体内测量和成像，作为无胸腺裸鼠中实体瘤异种移植物生长的硫醇。结果将使能够更好地了解卵巢癌中耐药性的发展，并为有效治疗卵巢癌患者提供有效的诊断。