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Title: Investigations into the specificity and mechanism of action of the attenuated adenovirus dl1520 with particular reference to head and neck cancer
Author: Murley, S. E.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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Abstract:
This thesis is concerned with investigating the selectivity; mechanisms of action and optimisation of delivery of the novel anti-cancer agent dl1520 (previously called Onyx-015). dl1520 is an attenuated adenovirus which has been genetically modified to have a selective cytolytic action against tumour cells deficient in function of the p53 tumour suppresser protein. This action follows on from a localised, productive infection of the virus. As defects in p53 gene function are known to occur in at least 60% of human solid malignancies this makes selective targeting of such cells an ideal strategy for anti-cancer gene therapy. A clinical trial is reported which assessed the effect of administering a single injection of dl1520 directly into intra-oral squamous carcinomas. Virus was injected into one hemi-tumour with the other half being injected with saline to act as a control. An area of normal intra-oral mucosa was also injected with virus and biopsied at the time of excisional surgery of the tumour. Sections of these tissues (virus injected tumour; saline injected tumour and virus injected normal tissue) were processed to detect the presence of adenovirus using in-situ hybridisation and immunohistochemistry. It is shown that the virus is found preferentially in the tumour tissues rather than the normal tissue samples. Tumours were assessed for the presence of p53 mutations, and it is noted that more virus overall is detected in p53 mutant tumour samples, but this difference is not statistically significant. Levels of apoptosis, as assessed using the TUNEL satin, are significantly higher in the normal tissue biopsies, as opposed to the tumour specimens. The above results indicate that the dl1520 virus can be safely administered to patients with intra-oral carcinoma who are suitable for excisional surgery. Even after a direct injection of the virus into normal tissue, no significant side effects were recorded. We conclude that we have added further evidence to support the use of this agent as a novel anti cancer agent.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.659769  DOI: Not available
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