Telomere function and the radiosensitivity of squamous carcinoma of the head and neck

McCaul, James A. (2004) Telomere function and the radiosensitivity of squamous carcinoma of the head and neck. PhD thesis, University of Glasgow.

Abstract

This thesis considers whether the alteration of telomere function by manipulation of the telomerase enzyme can affect the radiosensitivity of in vivo derived SCCHN cells and hence whether telomere dysfunction inducing strategies are likely to be synergistic with ionising radiation in the management of SCCHN. The role of telomerase in radioprotecting cancer cells is investigated using the ectopic expression of hTERT in cell lines with high and low levels of telomerase. The effect of inhibiting telomerase expression is examined using a dominant negative telomerase gene. This approach had little success in SCCHN cells and so further experiments designed to elaborate the effect of telomerase inhibition on radiosensitivity were carried out using the small molecule reverse transcriptase inhibitor 3’ – azido, 3’ – deoxythymidine (AZT). These showed both telomerase suppression and increased radiosensitivity in cells exposed to AZT in culture.

Other suggested factors which may affect the success of radiotherapy for cancer include the missense mutation of the p53 gene. A common polymorphism at codon 72 gives rise to Arginine or proline forms of the protein. This thesis investigates whether this variation affects radiosensitivity in SCCHN cells by assessing a panel of in vivo derived SCCHN cell lines.

If the level of telomerase expression does not impact on radiosensitivity, then the use of antitelomerase strategies may be less effective with higher levels of telomerase expression in tumours. Continued selective pressure during tumour progression may mean the emergence of clonal variants with improved telomere function via greater levels of telomerase. This is investigated by anaphase bridge scoring of primary and recurrent archival tumour material. Analysis of cells from primary lesions and then from recurrent disease in the same patient provides information in this regard.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Supervisor's Name: Parkinson, Dr. E. Ken
• Date of Award: 2004
• Depositing User: Angi Shields
• Unique ID: glathesis:2004-4117
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 18 Mar 2013 11:34
• Last Modified: 18 Mar 2013 11:34
• URI: https://theses.gla.ac.uk/id/eprint/4117