SECTION III: Other Aspects in Anticancer Therapeutic Development
19 Treatment of Cancer in Conjunction with Other Agents Gary Robert Smith 19.1 Introduction 19.2 Non-steroidal Anti-inflammatory Drugs 19.3 Angiotensin-converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockade 19.4 Partners in Crime - Dealing with Co-infections 19.5 Discussion
20 Clinical Trials in Oncology Tim Friede, Janet Dunn and Nigel Stallard 20.1 Clinical Trials 20.2 Early-Phase (Phase I and Phase II) Clinical Trials in Oncology 20.3 Confirmatory (Phase III) Trials in Oncology 20.4 Further Issues in Clinical Trials in Oncology
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311
314
317
317 318 320
322 324 329
331
332 341
347 349
349 353
358 362 363
365
365 368
374
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21 Representative Cancers, Treatment and Market
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CONTENTS
Teni Boulikas and Nassos Alevizopoulos
20 21.2 21.3 21.4 21.5 21.6 2457, 21.8 21.9
Lung Cancer
Breast Cancer
Prostate Cancer
Colorectal Cancer
Ovarian Cancer
Pancreatic Cancer
Gastric Cancer
Combination Chemotherapy
The Pharmaceutical World of Anticancer Drugs
Future Trends in Cancer Therapeutics Sotiris Missailidis
22.1 22.2 22.3 22.4
Index
Introduction Personalized Medicines Delivery Systems Closing Remarks
377
377
378 379 380 380
382 383
387
387 388 390 391
393
Foreword
There remains an urgent unmet clinical need to augment the efforts of surgeons and radiotherapists in combating localized malignant disease. Moreover, better strategies are required to deal with the all-too-common clinical scenario of patients presenting with disseminated metastatic disease, using systemic chemotherapy. In the 60-year history of cancer chemotherapy much has been achieved, particularly through the development of cytotoxic drugs in the 1950s and 1960s.
These are truly exciting times to be involved in anticancer therapeutics. Many would consider that we are now firmly in the second ‘golden age’ of discovering and developing new treatments for cancer. Such therapies represent the fruits arising from the elucidation of the cancer genotype and phenotype at the molecular and cellular level. This has led to the identification of a plethora of new cancer targets involved in growth signaling, angiogenesis and apoptosis. Notable recent success stories incl ude chimeric (human/mouse) or humanized monoclonal antibodies such as rituximab, trastuzumab and bevacizumab and small molecule kinase inhibitors such as imatinib, erlotinib, sunitinib and sorafenib. These new drugs are making amarked impact in modern chemotherapeutic regimes. However, significant improve- ments are still required in the process of translating new targets through preclinical discovery and development and into a successful clinical outcome. Evidence suggests that many drugs entering the clinic fail to reach approval for reasons of poor pharmacology, lack of efficacy or unacceptable adverse effects.
The following chapters provide an insight into state-of-the art methodologies to discov- ering new drugs including combinatorial approaches, natural product libraries and in silico techniques. Thereafter, there is a comprehensive guide through traditional cytotoxic drugs (platinum drugs, antimetabolites, tubulin interactive agents, alkylating agents, antitumour antibiotics), hormone and photodynamic therapies and recently approved molecularly- targeted drugs, both small molecules and monoclonal antibody-based. There are also reviews of the important areas of tumour drug resistance and tumour hypoxia. In addition, a glimpse of the future is provided through considerations of new approaches currently under study at the preclinical and early clinical level; these include cancer vaccines, gene therapy, antisense agents and aptamers. Finally, clinical practice issues are described; combination treatments, trials and a focus on particular major cancers.
The current excitement and optimism of improvements in patient benefit arising from modern cancer chemotherapy are illustrated herein. The present trend continues to build on exploiting the molecular hallmarks of cancer; three of the four drugs approved by the US FDA in 2007 were the kinase inhibitors nilotinib and lapatinib and the mTOR inhibitor tem- sirolimus. In addition, evidence to support a view that new cytotoxics also have a place in
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xiv FOREWORD
contemporary cancer drug development is provided by the 2007 FDA approval of the anti- tubulin epothilone, ixabepilone. There is also considerable attention being paid to the effective combination usage of molecularly-targeted drugs with traditional cytotoxics (for example, with the approval of the angiogenesis inhibitor antibody bevacizumab, with carboplatin and paclitaxel in patients with non-small cell lung cancer). In parallel, there is increasing empha- sis being placed on the individualization of treatment options with the identification and use of prognostic and treatment response biomarkers.
There has never been a better era to be involved in discovering and developing anticancer drugs.
Lloyd R. Kelland
Head of Biology
Cancer Research Technology University College London London, UK
Acknowledgements
There are a number of people that | would like to acknowledge for their contribution in the completion of this volume. First of all, | would like to acknowledge my wife Dr Giselle Martins dos Santos Ferreira and our daughter Ananda for their patience and support during the frantic time of putting this volume together. | could not have done it without their support and encouragement.
For this volume to be compiled, it took a great many authors, specialists in their field, who volunteered their time when all are busy with their jobs. | would like to thank them for preparing very interesting and comprehensive pieces of work, working meticulously and with good timing to see this effort completed within the time plan that was originally agreed and at the highest standard. | thank all the authors of their chapter contributions. They made the volume what | hope to be a very interesting, informative and authoritative work.
Finally, | would like to thank the team at Wiley, Rachael Ballard, Liz Renwick, Fiona Woods and Robert Hambrook, as well as our editor, Alison Woodhouse, who have guided me through the various stages of this process and with whom | have worked so well in the preparation of this volume and are already preparing the next.
Sotiris Missailidis The Open university, UK
List of Contributors
Stefano Alcaro
Laboratorio di Chimica Farmaceutica Dipartimento di Scienze Farmacobiologiche Universita di Catanzaro ‘Magna Greecia’ Roccelletta di Borgia (CZ), Italy
Anna Artese
Laboratorio di Chimica Farmaceutica Dipartimento di Scienze Farmacobiologiche Universita di Catanzaro ‘Magna Grecia’ Roccelletta di Borgia (CZ), Italy
Maria Belimezi Regulon Inc. (USA) Afxentiou 7, Alimos Athens, Greece
Evagelos Bellis Regulon Inc. (USA) Afxentiou 7, Alimos Athens, Greece
K. Eszter Borbas
Department of Chemistry
North Carolina State University Raleigh, NC, USA
David Bouchier-Hayes
RCSI Education and Research Unit Beaumont Hospital
Dublin, Ireland
Teni Boulicas Regulon Inc. (USA) Afxentiou 7, Alimos Athens, Greece
Tracey Bradshaw
Centre for Biomolecular Sciences School of Pharmacy
University of Nottingham Nottingham, UK
Laura Breen
National Institute for Cellular Biotechnology (NICB)
Dublin City University
Dublin, Ireland
Petros Christofis Regulon Inc. (USA) Afxentiou 7, Alimos Athens, Greece
Paul Cordopatis
Laboratory of Pharmacognosy and Chemistry of Natural Products
Department of Pharmacy
University of Patras
Patras, Greece
Janet Dunn
Warwick Medical School The University of Warwick Warwick, UK
Ana Paula Francisco CECF, Faculty of Pharmacy University of Lisbon Lisboa, Portugal
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xviii LIST OF CONTRIBUTORS
Tim Friede
Warwick Medical School The University of Warwick Warwick, UK
David Kerr
Department of Clinical Pharmacology University of Oxford
Old Road Campus Research Building Oxford, UK
Huma Khan
Department of Chemistry and Analytical Sciences
The Open University
Milton Keynes, UK
Dorothée Lahaye
Department of Chemistry
North Carolina State University Raleigh, NC, USA
Fotini N. Lamari
Laboratory of Pharmacognosy and Chemistry
of Natural Products Department of Pharmacy University of Patras Patras, Greece
Vaidehi Makwana
Department of Chemistry and Analytical Sciences
The Open University
Milton Keynes, UK
Eduarda Mendes
CECF, Faculty of Pharmacy University of Lisbon Lisboa, Portugal
Nikolaos V. Michalopoulos
Medical School
University of Athens,
Athens, Greece
Sotiris Missailidis
Department of Chemistry and Analytical Sciences
The Open University
Milton Keynes, UK
Rui Moreira
CECF, Faculty of Pharmacy University of Lisbon Lisboa, Portugal
Robert O'Connor
National Institute for Cellular Biotechnology
(NICB) Dublin City University Dublin, Ireland
Jill L. O'Donnell
RCSI Education and Research Unit Beaumont Hospital
Dublin, Ireland
Francesco Ortuso
Laboratorio di Chimica Farmaceutica
Dipartimento di Scienze Farmacobiologiche
Universita di Catanzaro ‘Magna Grecia’
Roccelletta di Borgia (CZ), Italy
Alexandros Pantos Regulon Inc. (USA) Afxentiou 7, Alimos Athens, Greece
Manuel M. Paz
Department of Organic Chemistry Faculty of Science
University of Santiago de Compostela Lugo Campus
Lugo, Spain
Maria de Jesus Perry CECF, Faculty of Pharmacy University of Lisbon Lisboa, Portugal
Michael L. Roberts Regulon Inc. (USA) Afxentiou 7, Alimos Athens, Greece
Jessica Scaiffe
ST2 Core Medical Training Department of Oncology Cheltenham General Hospital Cheltenham, UK
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LIST OF CONTRIBUTORS xix
Andrew Schofield
School of Medicine
College of Life Sciences and Medicine University of Aberdeen
Aberdeen, UK
Aoife M. Shannon
RCSI Education and Research Unit Beaumont Hospital
Dublin, Ireland
Suzanne Simmons
Department of Chemistry and Analytical Sciences,
The Open University,
Walton Hall,
Milton Keynes, UK
Gary Robert Smith Perses Biosystems Ltd Warwick, UK
Nigel Stallard Warwick Medical School The University of Warwick, UK
Flora Zagouri Medical School University of Athens Athens, Greece
George C. Zografos Medical School University of Athens, Athens, Greece