In Vivo EPR Imaging of Redox Status and Thiols in Tumor

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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.