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Oncolytic Adenovirus Vectors for Nitroreductase Suicide Gene Therapy of Prostate Cancer

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Oncolytic Adenovirus Vectors for Nitroreductase Suicide Gene Therapy of Prostate Cancer Oncolytic Adenovirus Vectors for Nitroreductase Suicide Gene Therapy of Prostate Cancer Morgan Reece Herod A thesis submitted to the School of Cancer Sciences of the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School for Cancer Sciences College of Medical and Dental Sciences University of Birmingham June 2010 I University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Prostate cancer is the most common male cancer in the UK and USA, with a 1/13 chance of diagnosis and a 1/30 lifetime risk of death from the disease. Current treatment options include radiotherapy, surgery and hormone therapy, however 1/3 patients escape from all therapies and novel therapies are urgently required for this patient group. The University of Birmingham gene therapy group constructed two oncolytic adenovirus vectors, CRAd-NTR and vNR6, both of which contained the E1B-55K deletion and expressed the transgene nitroreductase for combined oncolytic virotherapy and enzyme/prodrug gene therapy. The latter of these two vectors, vNR6, expressing nitroreductase from the pIX virus promoter demonstrated the greatest cytotoxicity at low virus concentrations however also showed some lytic activity to non-transformed human fibroblasts. Our collaborators at the Institut Català d'Oncologia designed a panel of oncolytic adenovirus vectors with the E1A CR2 24 deletion and the E1A promoter replaced by an insulated E2F-1 promoter. The latest two in this series of vectors, termed ICOVIR-5 and ICOVIR-7, provide potential oncolytic backbones for the introduction of the therapeutic transgene nitroreductase. The aim of this thesis was therefore to „arm‟ the ICOVIR based vectors with nitroreductase for combined oncolytic virotherapy and enzyme/prodrug therapy. At the beginning of this study no reports were published with either ICOVIR-5 or ICOVIR-7 based vectors. It was therefore first decided to construct both vectors expressing the marker transgene eGFP. These vectors were characterised in terms of cytotoxicity, transgene expression, DNA replication and E1A expression. Furthermore, these vectors were compared to the vNR3, an E1B-55K deleted virus similar to vNR6, but the eGFP ORF replacing that of pIX. The ICOVIR-7 based vectors were identified as being the most tumour selective vectors and demonstrated no cytotoxicity to non-transformed human fibroblasts, and were therefore chosen for the II introduction of the therapeutic transgenes. The new ICOVIR-7 based vectors were constructed to express either wildtype, double mutant or triple mutant nitroreductase. Double and triple mutant nitroreductase are two previously characterised mutant nitroreductases, which show enhanced catalytic activity for the prodrug CB1954. The new nitroreductase expressing ICOVIR-7 vectors were characterised in terms of virus mediated cytotoxicity, tumour selectivity, E1A and NTR expression and cytotoxicity with the prodrug CB1954. One vector, expressing double mutant nitroreductase, showed the highest tumour selectivity and greatest combined cytotoxicity with the prodrug CB1954. Furthermore, this vector showed greater tumour selectivity and combined cytotoxicity than the E1B-55K deleted vector vNR6. III Acknowledgements I would like to thank my supervisors Drs Vivien Mautner and Peter Searle for their guidance throughout my PhD, the critical reading of this thesis and being excellent mentors through the three years. I would also like to thank the gene therapy group for providing a pleasurable and stimulating working environment and supplying three years worth of good times outside the lab. In particular, I would like to mention David Onion and Simon Vass for their generous support and help in the lab. IV Table of Contents CHAPTER 1 Introduction ................................................................... 1 1.1 Gene Therapy ................................................................................................... 2 1.1.1 Monogenic Diseases ................................................................................... 2 1.1.1.1 Cystic Fibrosis ....................................................................................... 3 1.1.1.2 SCID-X1 ................................................................................................ 4 1.1.1.3 Adenosine Deaminase (ADA) Deficiency ............................................. 5 1.1.2 Other Gene Therapy Targets .................................................................... 6 1.1.3 Cancer Gene Therapy ................................................................................ 7 1.1.3.1 Cancer Gene Therapy Vectors ............................................................... 8 1.1.3.1.1 Non-Viral Vectors ......................................................................... 9 1.1.3.1.2 Viral Vectors ................................................................................. 9 1.1.3.1.2.1 Retrovirus ...................................................................................... 9 1.1.3.1.2.2 Herpes Simplex Virus ................................................................. 12 1.1.3.1.2.3 Adeno-Associated Virus ............................................................. 15 1.1.3.1.2.4 Adenovirus .................................................................................. 18 1.2 Adenovirus ...................................................................................................... 19 1.2.1 Capsid Structure and Organisation ....................................................... 20 1.2.2 Core Structure and Genome Organisation ............................................ 25 1.2.2.1 Early Gene Expression ......................................................................... 26 1.2.2.1.1 E1 ................................................................................................ 26 1.2.2.1.2 E2 ................................................................................................ 31 1.2.2.1.3 E3 ................................................................................................ 32 1.2.2.1.4 E4 ................................................................................................ 35 1.2.2.2 Intermediate Gene Expression ............................................................. 39 1.2.2.3 Late Gene Expression .......................................................................... 41 1.2.3 Adenovirus Lytic Life Cycle ................................................................... 45 1.2.4 Current Adenovirus Cancer Gene Therapy Strategies ........................ 55 1.2.4.1 Replication Deficient Adenovirus Vectors .......................................... 56 1.2.4.1.1 p53 Tumour Suppressor Replacement ........................................ 58 1.2.4.1.2 Enzyme – Prodrug Therapy ........................................................ 59 1.2.4.1.2.1 Herpes Simplex Virus Thymidine Kinase – Ganciclovir ........... 60 1.2.4.1.2.2 Cytosine deaminase – 5-Flurocytosine ....................................... 63 1.2.4.1.2.3 Nitroreductase – CB1954 ............................................................ 63 1.2.4.2 Oncolytic Adenoviruses ....................................................................... 66 1.2.4.2.1 Adenovirus Gene Deletions ........................................................ 66 1.2.4.2.2 Promoter Replacements .............................................................. 70 1.2.4.3 Oncolytic Adenoviruses Carrying Transgenes .................................... 73 1.2.4.4 Improved Adenovirus Systems ............................................................ 74 1.2.4.4.1 Retargeting to Tumours .............................................................. 74 1.2.4.4.2 Improving Tumour Specificity ................................................... 78 1.2.4.4.3 Improving Enzyme-Prodrug Systems ......................................... 82 1.3 Prostate Cancer Gene Therapy .................................................................... 84 V 1.3.1 The Prostate and Prostate Cancer .......................................................... 84 1.3.2 Molecular Mechanisms of Prostate Cancer ........................................... 85 1.3.3 Current Prostate Cancer Therapy ......................................................... 87 1.3.4 Gene Thereapy Stratergies for Prostate Cancer ................................... 88 1.4 Aims of Thesis ................................................................................................ 90 CHAPTER 2 Materials and Methods ...............................................91 2.1 Suppliers of Materials .................................................................................... 92 2.2 Molecular Cloning ......................................................................................... 92 2.2.1 Restriction Endonuclease Digestion of DNA ......................................... 92 2.2.2 Phenol/Chloroform Extraction ............................................................... 92 2.2.3 Precipitation
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