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Investigating genetic mechanisms of cisplatin resistance in neuroblastoma cell lines

Toutoudaki, Andriana (2017) Investigating genetic mechanisms of cisplatin resistance in neuroblastoma cell lines. Master of Science by Research (MScRes) thesis, University of Kent,. (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:63934)

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Language: English

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Abstract

Cancer therapy development has improved the survival rate of patients over the past few decades. The major limitation of this approach is the inevitable emergence of resistance upon patient relapse. Acquired drug resistance can develop over the course of treatment causing tumours to no longer respond to therapy. There are several mechanisms that have been proposed to contribute to this development. Platinum compounds, a major class of chemotherapy agents, are used in approximately half of all chemotherapy schedules. Cisplatin is an alkylating-like agent that causes DNA damage by binding to purine bases and forming DNA lesions, eventually leading to cell death. Regardless of cisplatin's efficacy, there two major limitations for its use, severe cytotoxic side effects and the inevitable formation of drug resistance. For this project, two neuroblastoma cell lines UKF-NB-3 and UKF-NB-6, derived from late-stage high-risk neuroblastoma patients, have been adapted to cisplatin in order to investigate the emergence of resistance. Using next generation sequencing analysis tools, the parental sensitive cell lines have been analysed and compared to their cisplatin resistant sublines in order to identify key variations that could account for the emergence of resistance to cisplatin. In both resistant sublines, mutations in solute carrier proteins and calcium gated channels were found to be increased, suggesting effects on drug uptake and adaptation to tumour microenvironment. In addition, only in UKF-NB-3rCDDP1000, pathways associated with the structure and synthesis of the extracellular matrix where highly mutated which is predicted to alter drug uptake and efflux. Finally, in UKF-NB-6rCDDP2000 affected pathways included surface MHC-1 downregulation and dysregulation of glycogen metabolism, both predicted to contribute to the emergence of cisplatin resistance.

Item Type: Thesis (Master of Science by Research (MScRes))
Thesis advisor: Wass, Mark N.
Thesis advisor: Michaelis, Martin
Uncontrolled keywords: cancer genomics, neuroblastoma, drug resistance
Divisions: Faculties > Sciences > School of Biosciences
SWORD Depositor: System Moodle
Depositing User: System Moodle
Date Deposited: 10 Oct 2017 14:10 UTC
Last Modified: 29 May 2019 19:40 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/63934 (The current URI for this page, for reference purposes)
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