E1B attenuated adenoviral therapy for recurrent squamous cell cancer of the head and neck

Ganly, Ian (2001) E1B attenuated adenoviral therapy for recurrent squamous cell cancer of the head and neck. MD thesis, University of Glasgow.

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Abstract

Recurrent head and neck cancer is a disease which causes significant morbidity and mortality. Despite advances in surgical reconstruction and in chemotherapy and radiotherapy, current treatments for this disease give poor responses which are of short duration. Because of this, there is a need for new biological therapies to be developed. An example of this is the E1B deleted adenovirus, Onyx-015, which has been shown to selectively replicate in and lyse cells with non-functional p53 (Bischoff et al,1996). This virus may be therapeutically useful in the treatment of a wide range of tumours since p53 abnormalities are very common in human cancer. The aims of this thesis were to determine if this virus would selectively replicate in and lyse head and neck squamous cell carcinoma cell lines with non-functional p53, to determine if the virus could cause tumour regression of subcutaneous tumours derived from human head and neck tumour cell lines in a nude mouse xenograft model, and lastly to determine if this virus could be given safely by intratumoural injection to patients with recurrent head and neck cancer and whether it could produce an anti-tumour response. Using a panel of human head and neck squamous cell carcinoma cell lines of known p53 sequence and function, replication of the E1B attenuated adenovirus, Onyx-015, was tested by cytopathic effect assays, hexon protein staining and quantified by flow cytometry. These assays showed that replication was more efficient in cell lines with non-functional p53 confirming the previously published work in other cell types by Bischoff et al,1996. The cell line BICR16, derived from a patient with recurrent head and neck cancer, was used for in-vivo testing by intratumoural injection of subcutaneous xenografts in nude mice. We showed tumour regression in all virus injected tumours. In contrast, diluent injected tumours continued to grow exponentially. To determine the incidence of p53 inactivation in recurrent head and neck cancer, the p53 status of 22 recurrent head and neck tumours was evaluated by gene sequencing, mdm2 expression and HPV expression. Overall we have shown that there is a greater incidence of p53 mutations in recurrent disease compared to primary disease. However the incidence of HPV infection and mdm2 overexpression was similar to reported studies in primary disease. Nevertheless, we show that the overall incidence of p53 alterations is very high at 95%. This may be one factor which accounts for the poor response of this disease to radiotherapy and chemotherapy and implies new therapies which either restore p53 function or which act in a p53 independent manner may prove to be beneficial in this disease. (Abstract shortened by ProQuest.).

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: David Soutar
Keywords: Pharmacology, Oncology
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-72009
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 May 2019 13:26
Last Modified: 17 May 2019 13:26
URI: http://theses.gla.ac.uk/id/eprint/72009

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