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Title: The role of death receptor ligation and signal transduction inhibition in the killing of leukaemia cells by cytotoxic drugs and radiation
Author: Jones, Dylan Trefor
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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In order to establish effective therapies for leukaemia, it is crucial to understand and exploit mechanisms of apoptosis regulation involving death receptors and other signalling mechanisms. In some leukaemia cell lines, cytotoxic drugs induce expression of the death receptors (DRs) Fas or DR5, which may contribute to apoptosis via ligation by Fas ligand (Fas-L) or TRAIL respectively. Although Fas mRNA expression in B-CLL cells was elevated following cytotoxic treatments, only γ-irradiation increased Fas protein levels. AML cells expressed Fas protein with no change being observed following treatment. None of the treatments induced Fas-L expression. An agonistic anti-Fas monoclonal antibody (CH-11) induced apoptosis in AML cells only, with no synergistic apoptosis in combination with cytotoxic agents. AML, but not CLL, cells were sensitive to TRAIL, with synergistic apoptosis in combination with cytotoxic drugs. Pro-caspase-8 processing in B-CLL and AML cells was induced by all of the cytotoxic stimuli even in the absence of ligation of Fas or DRs. The data suggests that the Fas and DR signalling system does not play a major role in the induction of apoptosis in B-CLL cells treated with cytotoxic agents. However, the apoptotic synergy observed with TRAIL and daunorubicin (DNR) in AML cells may have clinical significance. Despite the extended survival of B-CLL cells in-vivo, cells cultured in-vitro die rapidly by spontaneous apoptosis. The data here show that components of autologous plasma contribute to basal survival of B-CLL cells, and protect these cells from killing by the ansamycin antibiotic herbimycin A (HMA), the PI3-K inhibitor LY29400 or chlorambucil (Chl). Co-treatment of B-CLL cells with Chl and either HMA or LY294002 reduced the Chl LD50 (lethal dose, 50% viability) significantly. The data suggest that plasma activation of the PI3-K/Akt pathway may abrogate p53 upregulation after Chl mediated DNA damage. Therefore, strategies designed to inhibit plasma-induced anti-apoptotic signalling are likely to be of value in the design of novel therapeutic protocols.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available