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Title: A study of the novel VDEPT cancer gene therapy combination nitroreductase / CB1954 : mechanisms of cell death, modulation of cellular signalling pathways and early phase clinical trials
Author: Palmer, Daniel Harrison.
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2003
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A major limitation to the success of cancer gene therapy is the low efficiency of gene delivery achieved by currently available vectors. Virus-directed enzyme prodrug therapy aims to overcome this limitation by delivery of an enzyme to the tumour site, which catalyses the conversion of an inert prodrug to a potent cytotoxic. Activation of the prodrug at the tumour site maximises local cell kill whilst minimising systemic toxicity. Importantly, the activated species should pass to neighbouring nontransduced cells to mediate 'bystander' killing. In this way, significant anti-tumour effects may be observed even when only a fraction of cancer cells express the enzyme. A novel VDEPT system utilises bacterial nitroreductase (NR) to convert the monofunctional alkylating agent CB 1954 to a highly potent bifunctional agent. This is the first clinical experience of this combination, using a replication defective adenovirus to deliver NR. We report safety and kinetic data for prodrug and vector; host immune responses to vector; and extent of transgene expression. To facilitate the further development of this approach, we have investigated the mechanism of cell death induced by activated CB 1954, its interaction with conventional chemotherapeutic agents, and the effects of adenovirus vectors on key cellular pathways regulating cell survival and inflammatory/immune responses. We have identified synergistic cell killing with NRiCB 1954 and 5-fluorouracil, providing a rational framework for future clinical trial design. Adenovirus vectors (replicationdefective and conditionally-replicating) activate several signalling pathways, including PI3-kinase/Akt and NF-KB, mediating anti-apoptotic and inflammatory responses and significantly affecting therapeutic efficacy. Manipulation of signalling events presents a potential therapeutic target for the enhancement of adenovirus-based cancer gene therapy strategies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available