Host Factors in Ovarian Influencing Efficacy of dl922-947

Magdalena Barbara Flak

A submitted to the University of London (Faculty of Science) for the degree of Doctor of Philosophy

February 2010

Centre for Molecular Oncology and Imaging Institute of Cancer Barts and the London School of Medicine and Dentistry Charterhouse Square, London EC1M 6BQ

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I, Magdalena Barbara Flak, hereby confirm that the work presented in this thesis is original and is my own. Work undertaken by others in contribution to this thesis has been clearly indicated. Where information has been derived from other sources, this has been acknowledged and appropriately referenced.

Signed ………………………………...

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Acknowledgments

First of all, I would like to thank my supervisor Prof Iain McNeish. He has given me the opportunity to work on this exciting project. But more importantly, Iain, your expertise, encouragment and genuine support have guided me throughout my PhD and allowed me to grow as a scientist and as a person.

I owe my deepest gratitude to Jes, without whom I may not have come this far. Your support, neverending patience and love have carried me through the most frustrating, difficult times. Having you as a companion to celebrate the great moments made them all the more precious. You have always believed in me, and I am forever in your debt.

I would like to thank my parents. They were always, always there to listen, to share disappointments and successes. You have instilled in me the awe and curiosity of all things around me. You have dedicated your strength to letting me follow my ambitions. This thesis would not have been possible without you. Thomas, I thank you for brotherly supervision of my first “lab experiments” at home, mixing coloured water in test tubes, and for my first microscope. In short, for supporting a dream and putting things into perspective. Z całego serca dziękuję moim kochanym Babcią i Dziadką za pomyślność i modlitwe. Za miejsce w waszych sercach.

Many friends have supported me on my path to a PhD, for which I cannot thank enough. Anke has been patient, wise and wonderful from day one. I am grateful to Maren, Mary, Manuel and Charmaine for their great support. I thank Prof B. Volk for encouragment and inspiration.

Heartfelt gratitude goes to my wonderful colleagues and friends Kyra, Carin, AM, Sarah, Michael, Lynda, Katrina, Michelle and Claire, for lab wisdom, for listening to my wingeing, for laughter, midnight meetings and chocolate. You have made the past years cheerful and enjoyable. Never forget: Doppelt gemoppelt haelt besser.

I would like to thank Katrina, Claire, Sarah and Claude in particular, for contributing valuable work to this thesis. I am truly grateful for your genious heads and hands making these experiments happen.

It was an honour and a pleasure to work with all the great people that make the Centre for Molecular Ongology & Imaging. I am very thankful for generous help and interesting discussions. I have met some great people and friends amongst you. I thank all those, whose names do not appear here, despite their contribution to this PhD. Please forgive me.

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Abstract Adenoviral holds great potential for cancer treatment, but is limited by a lack of efficient vectors. dl922-947, an E1A CR2-deleted adenovirus, replicates selectively within and lyses cancer cells. It is believed that its selectivity depends upon abnormalities in the regulatory Rb pathway and subsequent G1/S checkpoint, observed in 90% of human . The cytotoxic efficacy of dl922-947 is greater than that of wild-type ade