Show simple item record

dc.contributor.advisorWilliams, John H. H.
dc.contributor.advisorHoyle, Christine
dc.contributor.authorDempsey, Nina C.*
dc.date.accessioned2010-03-01T08:53:30Z
dc.date.available2010-03-01T08:53:30Z
dc.date.issued2009-08
dc.identifieruk.bl.ethos.511081
dc.identifier.urihttp://hdl.handle.net/10034/93233
dc.description.abstractAlthough a number of HSPs have been shown to be up-regulated in a wide range of human cancers, the full significance of this remains to be determined. The localisation of HSPs seems to be critical in determining their role in cancer cell survival; High intracellular levels (iHsp) appear to be advantageous to the tumour cell, inhibiting key steps in apoptosis, while in some circumstances, surface expression (sHsp) appears to be detrimental to the cell, aiding immune recognition by various effector cells. Consequently, clarifying the importance of HSP cellular location in the cancer setting may lead to the development of novel therapies based upon manipulation of HSP localisation. This thesis had two major aims; (1) to investigate the cellular localisation of HSPs in leukocytes from patients with both myelocytic and lymphocytic malignancies in order to establish relationships between apoptosis and stage of disease (2) to study the synergistic effect of four chemotherapeutic drugs with membrane fluidising agents, compounds which have the potential to modulate HSP localisation. Hsp90 and Hsp27 expression was shown to be restricted to the inside of peripheral blood leukocytes, while Hsp72 was localised both intracellularly and on the cell surface. In CLL, iHsp90 and iHsp27 levels were found to be significantly higher than in control subjects, while surface and intracellular Hsp72 was shown to be expressed either at very high levels or at very low levels. Furthermore, iHsp90 levels were found to be associated with stage of disease, while iHsp27 levels were shown to negatively correlate with levels of apoptosis. CLL patients with stable disease were found to express higher levels of iHsp72 than patients with progressive disease. However, in AML and MDS, levels of all HSPs in peripheral blood were found to be similar to those seen in control subjects, but disease patients showed a much wider range of expression. In AML, levels of sHsp72 positively correlated in all cell types, an observation not made in MDS patients or control subjects. HSP localisation was shown to be affected by membrane fluidising agents, with a movement of Hsp72 and Hsp60 to the cell surface. This effect was not due to proteotoxicity and supports data implicating the cell membrane in the regulation of HSP responses. This manipulation of HSP localisation and the increase in membrane fluidity resulted in increased sensitivity of CLL cells to three chemotherapeutic agents and points to the possibility that manipulation of membrane fluidity, may have significant value in the development of new treatment regimes.
dc.language.isoenen
dc.publisherUniversity of Liverpool (University of Chester)
dc.subjectheat shock proteinsen
dc.titleLocalisation of heat shock proteins in haematological malignanciesen
dc.typeThesis or dissertationen
dc.type.qualificationnamePhDen
dc.type.qualificationlevelDoctoralen
html.description.abstractAlthough a number of HSPs have been shown to be up-regulated in a wide range of human cancers, the full significance of this remains to be determined. The localisation of HSPs seems to be critical in determining their role in cancer cell survival; High intracellular levels (iHsp) appear to be advantageous to the tumour cell, inhibiting key steps in apoptosis, while in some circumstances, surface expression (sHsp) appears to be detrimental to the cell, aiding immune recognition by various effector cells. Consequently, clarifying the importance of HSP cellular location in the cancer setting may lead to the development of novel therapies based upon manipulation of HSP localisation. This thesis had two major aims; (1) to investigate the cellular localisation of HSPs in leukocytes from patients with both myelocytic and lymphocytic malignancies in order to establish relationships between apoptosis and stage of disease (2) to study the synergistic effect of four chemotherapeutic drugs with membrane fluidising agents, compounds which have the potential to modulate HSP localisation. Hsp90 and Hsp27 expression was shown to be restricted to the inside of peripheral blood leukocytes, while Hsp72 was localised both intracellularly and on the cell surface. In CLL, iHsp90 and iHsp27 levels were found to be significantly higher than in control subjects, while surface and intracellular Hsp72 was shown to be expressed either at very high levels or at very low levels. Furthermore, iHsp90 levels were found to be associated with stage of disease, while iHsp27 levels were shown to negatively correlate with levels of apoptosis. CLL patients with stable disease were found to express higher levels of iHsp72 than patients with progressive disease. However, in AML and MDS, levels of all HSPs in peripheral blood were found to be similar to those seen in control subjects, but disease patients showed a much wider range of expression. In AML, levels of sHsp72 positively correlated in all cell types, an observation not made in MDS patients or control subjects. HSP localisation was shown to be affected by membrane fluidising agents, with a movement of Hsp72 and Hsp60 to the cell surface. This effect was not due to proteotoxicity and supports data implicating the cell membrane in the regulation of HSP responses. This manipulation of HSP localisation and the increase in membrane fluidity resulted in increased sensitivity of CLL cells to three chemotherapeutic agents and points to the possibility that manipulation of membrane fluidity, may have significant value in the development of new treatment regimes.
dc.rights.usageThe full-text may be used and/or reproduced in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-profit purposes provided that: - A full bibliographic reference is made to the original source - A link is made to the metadata record in ChesterRep - The full-text is not changed in any way - The full-text must not be sold in any format or medium without the formal permission of the copyright holders. - For more information please email researchsupport.lis@chester.ac.uk


Files in this item

Thumbnail
Name:
introductory materials.pdf
Size:
195.6Kb
Format:
PDF
Request:
Introductory Materials
Thumbnail
Name:
chapter 1.pdf
Size:
943.3Kb
Format:
PDF
Request:
Introduction
Thumbnail
Name:
chapter 2.pdf
Size:
284.5Kb
Format:
PDF
Request:
Materials & Methods
Thumbnail
Name:
chapter 3.pdf
Size:
487.0Kb
Format:
PDF
Request:
Heat Shock Protein Localisation ...
Thumbnail
Name:
chapter 4.pdf
Size:
600.2Kb
Format:
PDF
Request:
Heat Shock Protein Localisation ...
Thumbnail
Name:
chapter 5.pdf
Size:
893.2Kb
Format:
PDF
Request:
Synergistic Action of Chemothe ...
Thumbnail
Name:
chapter 6.pdf
Size:
543.7Kb
Format:
PDF
Request:
Membrane Regulation of the HSP ...
Thumbnail
Name:
chapter 7.pdf
Size:
210.1Kb
Format:
PDF
Request:
Discussion and Conclusion
Thumbnail
Name:
chapter 8.pdf
Size:
337.4Kb
Format:
PDF
Request:
References

This item appears in the following Collection(s)

Show simple item record