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dc.contributor.authorPower, Jenen
dc.date.accessioned2018-08-10T19:55:52Z
dc.date.available2018-08-10T19:55:52Z
dc.identifier.urihttp://hdl.handle.net/1974/24430
dc.description.abstractOvarian cancer is the fifth most common cancer in Canadian women and has the highest mortality rate of all gynecologic malignancies. First-line treatment is typically cytoreductive surgery followed by a combination of paclitaxel and carboplatin. Unfortunately, patients frequently relapse with drug resistant disease, and only 45% of patients survive beyond 5 years. Drug resistance results from multiple mechanisms, one of which is mediated by one or more of the ATP-binding cassette (ABC) drug efflux transporters. The two ABC transporters considered clinically relevant in ovarian cancer are P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1). These plasma membrane transporters can efflux an array of solutes from the cell, including paclitaxel. Extracellular vesicles (EVs) are a collective term for nano-sized membrane vesicles released from all mammalian cells that can serve as cell-free vehicles to deliver a variety of biomolecules to recipient cells. The human ovarian cancer cell lines A2780 and 2008, and their drug resistant variants, AD645 and 2008/MRP1, which overexpress P-gp and MRP1, respectively, were used to investigate whether transporter-containing EVs can transfer drug resistance to sensitive cells. All four cell lines were shown to release EVs isolated by differential ultracentrifugation (DUC) and size-exclusion chromatography (SEC), as indicated by the presence of EV markers CD63, CD81, and syntenin-1 in immunoblots of EV extracts. P-gp and MRP1 were also detected in EV extracts from AD645 and 2008/MRP1 cells, respectively. DUC- isolated AD645 EVs appeared toxic to A2780 recipient cells and there was no detectable transfer of paclitaxel resistance after co-culture. SEC-isolated AD645 EVs were more enriched than DUC-isolated EVs for CD63, CD81, and syntenin-1, and appeared less toxic to A2780 cells. However, P-gp was not enriched in SEC-isolated AD645 EVs and there was no detectable ii transfer of paclitaxel resistance or P-gp to A2780 cells. These observations suggest that the amount of functional P-gp transferred to recipient cells was insufficient to confer detectable resistance. These studies suggest that although P-gp and MRP1 can be detected in cellular material consistent with the presence of EVs, additional experiments are needed to optimize isolation of transporter-enriched EVs and co-culture conditions to detect the transfer of drug resistance.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectExtracellular Vesiclesen
dc.subjectOvarian Canceren
dc.subjectMultidrug Resistanceen
dc.subjectp-glycoproteinen
dc.titleThe role of extracellular vesicles in the transfer of multidrug resistance in human ovarian cancer cellsen
dc.typethesisen
dc.description.degreeM.Sc.en
dc.contributor.supervisorCole, Susanen
dc.contributor.departmentPathology and Molecular Medicineen
dc.degree.grantorQueen's University at Kingstonen


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