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Title: Apoptosis and mitotic slippage following drug intervention in leukaemia cells
Author: Omar, Najood Amer
ISNI:       0000 0004 2725 1440
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2011
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The response of leukaemia cells to therapeutic agents includes cell cycle arrest and apoptosis. The former response is useful in retarding disease progression, but induction of the latter is essential for disease eradication. Cell death is often related to toxicity so reducing drug-concentration or sensitising target cells to apoptosis is desirable. The relationship between the cell cycle and cell death has been at the centre of recent investigation focusing on mechanisms of cell death that are not driven directly by apoptotic responses. These mechanisms included mitotic catastrophe and mitotic slippage. The K562 myeloid leukaemia cell line exhibits a combination of p53 negativity and carries the Bcr-Abl t (9:22) Philadelphia chromosome. Bcr-Abl is a powerful anti-apoptotic translocation and is the hallmark of chronic myeloid leukaemia (CML). The absence of p53-mediated apoptosis and the anti-apoptotic effects of Bcr-abl delays drug-induced cell death, leaving a window of opportunity to investigate the effects of different agents on leukaemia cells. My investigations show that when DNA-targeting agents are used against myeloid leukaemia cells, G2 cell cycle arrest and apoptosis do not occur together i.e. cell cycle arrest precludes cell death; cells may escape G2 arrest as a result of mitotic slippage. In contrast, when anti-mitotic agents are used, it is necessary to induce mitotic arrest to subsequently induce apoptosis; thus lower concentrations are more effective in inducing apoptosis than higher drug concentrations. Evidence is provided suggesting reduced concentrations of both genotoxic agents and anti-mitotic agents may share a common pathway in inducing cell death that is related to events at mitosis and I suggest that this pathway has potential for exploitation by new agents currently in clinical trials, such as UCN-01, Purvanol, Roscovitine and agents that target the passenger proteins, in reducing the concentration of more conventional agents required to kill the Bcr-Abl positive leukaemias.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine