Chemosensitization of Hepatocellular Carcinoma to Gemcitabine By Non-Invasive Radiofrequency Field-Induced Hyperthermia

<p>Gemcitabine is a potent nucleoside analogue against solid tumors however drug resistance rapidly emerges. Removal of gemcitabine incorporated in the DNA by repair mechanisms could potentially contribute to resistance in chemo-refractory solid tumors. In this study, we evaluated homologous recombination repair of gemcitabine-stalled replication forks as a potential mechanism contributing to resistance. We also studied the effect of hyperthermia on homologous recombination pathway to explain the previously reported synergy between gemcitabine and hyperthermia. We found that hyperthermia degrades and inhibits localization of Mre11 to gemcitabine-stalled replication forks. Furthermore, gemcitabine-treated cells that were also treated with hyperthermia demonstrate a prolonged passage through late S/ G2 phase of cell cycle in comparison to cells treated with gemcitabine alone. This coincides with inhibition of resolution of γH2AX foci. Our findings also demonstrate that thermal sensitization of human hepatocellular carcinoma cell lines to gemcitabine is mediated through an Mre11-dependent homologous recombination repair pathway. Combination of non-invasive radiofrequency field-induced hyperthermia and gemcitabine was superior to either therapy alone (p</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2012

Author dc:creator

• Raoof, Mustafa

Contributors dc:contributor

• Steven A. Curley, MD
• Gary E. Gallick, PhD
• Anil Sood, MD

• gemcitabine
• stalled replication fork
• homologous recombination
• hyperthermia
• radiofrequency
• hepatocellular carcinoma
• Genetic Processes
• Hepatology
• Laboratory and Basic Science Research
• Medical Pharmacology
• Medicine and Health Sciences
• Molecular Biology
• Neoplasms
• Nucleic Acids, Nucleotides, and Nucleosides
• Pharmacology
• Surgery

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/244

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1271