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Title: Cellular response to topoisomerase-targeting antraquinones
Author: Blunt, N.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1997
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Quiescent, or G0, cells are present as subpopulations within some solid human tumours and exhibit innate resistance to a range of anticancer agents including those which target the enzyme DNA topoisomerase II. They are thought to be chemoresistant due to a) the decreased levels of the target enzyme, b) a requirement for active cell cycle progression for the fixation and recognition of cellular damage and c) the pharmacodynamics of the agent. Drugs which can persistently target DNA cause cellular effects over a time period which extends beyond the initial exposure to drug. Persistence is an important factor for topoisomerase-interactive agents since growth factor stimulation of quiescent breast tumour cells, for example, is associated with an elevation of target enzyme levels. This thesis addresses the effects of topoisomerase inhibition in both asynchronous and quiescent cultures using anthraquinones which persistently trap topoisomerase IIα and induce DNA damage, and uses the techniques of flow cytometry and confocal imaging to examine the subcellular distribution and persistence of these agents. N-oxide derivatives of these agents have been evaluated in an attempt to develop drugs which can be bioreductively-activated under hypoxic conditions to produce persistent topoisomerase II poisons which selectively target G0 cells. The dioxopiperazine, ICRF-193 prevents enzyme activity without generating DNA damage, and has enabled us to investigate the role of DNA topoisomerase IIα in the formation of drug-induced damage. The studies were carried out in a human breast tumour cell system which presented differences in checkpoint integrity, by virtue of p53 mutation, and resistance associated with modified topoisomerase II expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available