DOI
https://doi.org/10.25772/3W3K-4E53
Defense Date
2010
Document Type
Thesis
Degree Name
Master of Science
Department
Physiology
First Advisor
Paul Dent
Abstract
Renal cell carcinoma accounted for an estimated 57,760 new cases and estimated 12,980 deaths in the United States in 2009. Current treatment options for systemic renal cell carcinoma yield markedly low response percentages; however, recent cytokine therapy experiments have produced promising results. A novel adenovirus, Ad.5/3-mda-7, has been synthesized to efficiently infect renal cancer cells with the mda-7 gene. This gene encodes for the cytokine MDA-7/IL-24 that has the ability to specifically target transformed cells. Assays performed with this adenovirus resulted in an increased percentage of cell death in renal cancer cells when compared to infection with Ad.5/3-cmv empty vector. Further assays that combined Ad.5/3-mda-7 infection with treatments of small molecule inhibitors increased the percentages of cell death by upregulating JNK and p38 MAPK pathways, downregulating the ERK1/2 MAPK pathway, and downregulating the PI3K pathway. Western blots confirmed upregulation and downregulation of these pathways by probing for key proteins. Renal cancer cells responded best to infection with Ad.5/3-mda-7 and treatment with PD184352, PX866, and Rapamycin. This combinatorial treatment caused a greater percentage of cell death than the sum of the two individual treatments, suggesting a synergistic inhibition of cell growth pathways. These findings suggest that the combination of Ad.5/3-mda-7 and specific small molecule inhibitors has developmental potential as a novel and more efficient treatment option for systemic renal cell carcinoma.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
April 2010