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SYNERGISM VIA REACTIVE OXYGEN SPECIES OF FENRETINIDE
COMBINED WITH OTHER ANTI-NEOPLASTIC AGENTS IN PRECLINICAL
MODELS OF RECURRENT NEUROBLASTOMA
by
Nancy Tran
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(SYSTEMS BIOLOGY AND DISEASE)
August 2010
Copyright 2010 Nancy Tran
Object Description
| Title | Synergism via reactive oxygen species of fenretinide combined with other anti-neoplastic agents in preclinical models of recurrent neuroblastoma |
| Author | Tran, Nancy |
| Author email | nancytra@usc.edu; ntran82@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Systems Biology & Disease |
| School | Keck School of Medicine |
| Date defended/completed | 2010-06-10 |
| Date submitted | 2010 |
| Restricted until | Restricted until 05 Aug. 2012. |
| Date published | 2012-08-05 |
| Advisor (committee chair) | Johnson, Deborah L. |
| Advisor (committee member) |
Ladner, Robert D. Seeger, Robert C. Reynolds, Charles Patrick |
| Abstract | Neuroblastoma is the most common extracranial solid tumor of childhood and the most frequently diagnosed malignancy during infancy. It accounts for more than 7% of all childhood malignancies in the United States and 15% of all pediatric oncology deaths. Half of neuroblastoma patients present with a high-risk phenotype at diagnosis and overall survival for this patient population is poor. Even with recent advancements in neuroblastoma therapy in the past few decades, challenges remain as many high-risk patients respond to initial treatment only to relapse and succumb to refractory disease. Most recurrent high-risk neuroblastomas manifest multi-drug resistance to the drugs employed in therapy. Thus, there is a critical need to develop new non-cross-resistant drugs and drug combinations active against multi-drug resistant, recurrent neuroblastoma.; In this study, I identified drugs that showed synergistic cytotoxicity with the cytotoxic retinoid N-(4-hydroxyphenyl)retinamide (fenretinide; 4-HPR) in preclinical models of recurrent neuroblastoma. I first evaluated the combination of 4-HPR with ABT-751, an oral colchicine-binding site microtubule inhibitor; a drug combination that proved to be synergistic and highly active in neuroblastoma murine xenografts. I identified the mechanism of synergistic cytotoxicity (via enhanced tumor cell apoptosis due to 4-HPR-generated reactive oxygen species (ROS)) and expanded the study to examine 4-HPR in combination with four clinically available microtubule inhibitors – vincristine, vinorelbine, paclitaxel, and colchicine. Lastly, I evaluated the efficacy of combining 4-HPR with buthionine sulfoximine, which generates ROS in neuroblastoma due to the depletion of glutathione. These studies demonstrate that the ROS production by 4-HPR can enhance the activity of other anti-neoplastics, especially microtubule inhibitors. |
| Keyword | neuroblastoma; fenretinide; microtubule inhibitors; cancer therapeutics |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3306 |
| Rights | Tran, Nancy |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Tran-3869 |
| Archival file | uscthesesreloadpub_Volume44/etd-Tran-3869.pdf |
Description
| Title | Page 1 |
| Full text | SYNERGISM VIA REACTIVE OXYGEN SPECIES OF FENRETINIDE COMBINED WITH OTHER ANTI-NEOPLASTIC AGENTS IN PRECLINICAL MODELS OF RECURRENT NEUROBLASTOMA by Nancy Tran A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (SYSTEMS BIOLOGY AND DISEASE) August 2010 Copyright 2010 Nancy Tran |
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