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Title: Molecular therapy for residual squamous cancer
Author: Oakley, Ruth Elizabeth
ISNI:       0000 0001 3454 7045
Awarding Body: University of London
Current Institution: King's College London (University of London)
Date of Award: 2003
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A major problem in head and neck cancer management is the high rate of loco-regional recurrence following surgery and post-operative radiotherapy. Tumour cells that remain in the surgical margins are the likely source for this recurrence. Gene-mediated approaches, that take advantage of the genetic profile of these tumours, have the potential to eliminate these remaining cells. The high frequency of p53 mutation in head and neck cancers makes this gene a good candidate for therapy. The majority of residual cancer models used for treatment investigations are established subcutaneously in immunodeficient hosts. However, residual cancer models in muscle of immunocompetent hosts would more closely mimic the clinical scenario. In vitro studies established the suitability of the p53 mutated PDVC57 cell line for adenoviral-p53-mediated tumour destruction. PDVC57 cells showed 70% transduction efficiency. Polymerase chain reaction, Western blotting and immunocytochemistry confirmed the expression of the p53 transgene. Western blot analysis demonstrated increases in p21 WAFl, MDM2 and BAX proteins following Ad5CMV-p53 transduction. A significant reduction in PDVC57 number was observed following transduction of 625 vp/cell Ad5CMV-p53. The TUNEL assay and acridine orange/ethidium bromide incorporation suggested apoptotic death in 50010 and 70% of PDVC57 cells 48 hours after transduction with 2500 vp/cell Ad5CMV-p53 respectively. A new model of residual cancer was established by implanting 1 x 105 PDVC57 cells into the muscle of syngeneic immunocompetent hosts, and its reproducibility demonstrated. The reduction in tumour area following cisplatin treatment demonstrated the potential of this model for examining treatment efficacy. However, infection with 5 x 1010 vp Ad5CMV-p53 failed to destroy tumour in the muscle, likely due to the insufficient expression of the transgene. In comparison, Ad5CMV-p53 infection of a PDVC57 derived subcutaneous model of residual cancer, eliminated tumour in 4/6 cases. These studies highlight the requirement for improved gene delivery strategies for tumour in muscle.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available