Table Of Content

9219_C000a.fm Page i Thursday, October 19, 2006 8:27 AM 9219_C000a.fm Page ii Thursday, October 19, 2006 8:27 AM 9219_C000a.fm Page iii Thursday, October 19, 2006 8:27 AM 9219_C000a.fm Page iv Thursday, October 19, 2006 8:27 AM 9219_C000b.fm Page v Thursday, October 26, 2006 7:32 AM This book is dedicated to cancer patients worldwide who participate in Phase I clinical trials. Their valuable contribution furthers our knowledge of the treatment of cancer. Also, to members of my research group, past and present, who are a constant source of inspiration. 9219_C000b.fm Page vi Thursday, October 26, 2006 7:32 AM 9219_C000b.fm Page vii Thursday, October 26, 2006 7:32 AM Foreword Cancer is one of the most serious health problems in the Western Hemisphere. Significant progress in the development of novel drugs and therapies has occurred within the last 60 years and, thanks to the discovery of drugs such as cisplatin, the taxanes, and the nitrogen mustards in the last century, treatment of some forms of the disease has a high success rate, although patients must often tolerate unpleasant side effects. Only in the last decade has there been some success in developing “targeted” drugs and therapies with fewer side effects. For example, the recent discovery and rapid licensing of imatinib (Gleevec™) for the treatment of chronic myelogenous leukemia (CML) is often heralded as the start of a new era in the development of noncytotoxic agents targeted toward distinct biological pathways. However, despite these advances, the treatment of most types of solid tumors remains problematic and survival rates are, in general, disappointingly low. This book attempts to bring together a broad spectrum of information relating to the chemistry and pharmacology of anticancer drugs and therapies. The first chapter provides an introduction to cancer and includes a discussion of its causes, the problem of metastasis, its general modes of treatment, and the philosophy of drug discovery. The rest of the book provides a comprehensive survey of the various families of anticancer agents (including biological agents) in present use, some that are still at the research stage, and others that might be important in the future. Where possible, the different classes of anticancer agents are described in terms of their discovery, chemistry, mechanism of action, and some elements of structure activity relationships (SARs) through to pharmacology, clinical use, mechanism-based tox- icity, and relevant aspects of formulation and dose scheduling. The book is unique in providing the chemical structure of every drug discussed, including both those in clinical use and those at the research stage, and also in providing information on the side effects of most agents. A number of recent developments in research tools and methodologies that may help cancer researchers are also discussed, as are the relatively new areas of personalized treatments and chemoprevention. One of the difficulties in compiling a book of this nature is in deciding how to differentiate between agents in clinical use and those experimental agents at an earlier stage of development. Inevitably this has led to some difficult decisions as to whether certain agents should appear in Chapter 9 (The Future) or in other chapters relating to their class or mechanism of action. It is hoped that this book will have wide appeal for undergraduates, postgradu- ates, and practitioners in the health sciences (e.g., medicine, pharmacy, biomedical sciences, and nursing), and also for those studying pharmacology or specific areas of the natural sciences (e.g., the medicinal chemistry component of a chemistry course). Because the book contains sections on new research areas and tools, it should also be of interest to cancer researchers in both academia and industry. The 9219_C000b.fm Page viii Thursday, October 26, 2006 7:32 AM text stops short of providing detailed clinical aspects of treatments but contains sufficient information regarding dosing and side effects to be useful to medical, pharmacy, and nursing practitioners. After reading this book, it might be concluded that cancer chemotherapy has made spectacular progress since the discovery of the nitrogen mustards in the 1940s. However, in reality progress has been very poor given that more than 60 years have passed and still one in three of the population (at least in the West) develop cancer at some time in their lives and one in four die from the disease. Hopefully, this book will help to educate future generations of cancer researchers who will go on to discover more effective drugs and therapies. 9219_C000b.fm Page ix Thursday, October 26, 2006 7:32 AM Acknowledgments There are two origins to this book. First, it is based on lecture notes started at the College of Pharmacy at the University of Kentucky (Lexington, KY, U.S.A.) in 1981 (inherited from Professor Laurence Hurley), improved upon at the University of Texas at Austin College of Pharmacy (U.S.A.) from 1982 to 1986, and then consol- idated at the Pharmacy Schools of the Universities of Portsmouth, Nottingham, and London (U.K.) from 1987 to the present time, where they are still in use. These notes were initially summarized in a chapter in the book Smith and William’s' Introduction to the Principles of Drug Design & Action (now in its fourth edition [CRC Press, Boca Raton, FL, 2005]), and I am grateful to the editor, Dr. John Smith, and to Taylor & Francis for allowing me to use some of the material for this book. The other origin of this book is based on my period of service on the Cancer Research Campaign Grants Committee (now Cancer Research U.K.) from 1994 to 2005 and the Cancer Research U.K. New Agents Committee from 1998 to the present time. Throughout the years, membership on these committees has provided me with a wealth of background material and new concepts regarding both existing and novel therapeutic agents and strategies. Therefore, I would like to thank Professor Gordon McVie (then Director General of Cancer Research Campaign) for involving me with the charity’s scientific committees. I would also like to thank those mentors and colleagues who have influenced my career and thus contributed either directly or indirectly to this book. Although it is not possible to mention all by name, I would particularly like to thank Gerald Blunden, Colin Richards, Gary Thomas, David McIntyre, and the late Edwin Crundwell, all of whom first sparked my interest in research as an undergraduate. I am especially grateful to Laurence Hurley, who mentored me in my formative years and fostered my interest in anticancer drugs and DNA-interactive agents. Others who supported my career so generously in subsequent years and laid the foundation for this book to be written include Trevor Crabb, Ken Douglas, Sandy Florence, Angela Galpine, Ken Harrap, Chris Martin, Malcolm McVicar, Neil Merritt, John Midgley, Colin Monk, Stephen Neidle, Malcolm Stevens, and the late Tom Connors. I would also like to thank my close colleagues and collaborators John Hartley, Phil Howard, and Terry Jenkins for their friendship and support over the years. Phil Howard deserves a special mention as, without his tireless efforts throughout the years to supervise researchers and look after our laboratory so effectively, this book would never have been completed. John Smith and Clare Simons are also thanked for providing a significant input into Chapter 6 (Hormonal Therapies). I extend my gratitude to the British National Formulary (BNF) for providing information on dosing and adverse reactions. Sam Kneller is gratefully acknowledged for providing chemical structures and other material in support of parts of the text, as is Ruth Pickering for her outstanding assistance with preparing the manuscript, and