Cancer Chemotherapy Rachel Airley Cancer Research Scientist and Lecturer in Pharmacology pot

Cancer Chemotherapy Rachel Airley Cancer Research Scientist and Lecturer in Pharmacology Cancer Chemotherapy Cancer Chemotherapy Rachel Airley Cancer Research Scientist and Lecturer in Pharmacology This edition first published 2009 # 2009 by John Wiley & Sons Ltd Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s global Scientific, Technical and Medical business with Blackwell Publishing Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Other Editorial Offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book This publication is designed to provide accurate and authoritative information in regard to the subject matter covered It is sold on the understanding that the publisher is not engaged in rendering professional services If professional advice or other expert assistance is required, the services of a competent professional should be sought Library of Congress Cataloguing-in-Publication Data Airley, Rachel Cancer chemotherapy / Rachel Airley p ; cm Includes bibliographical references and index ISBN 978-0-470-09254-5 (HB) – ISBN 978-0-470-09255-2 (PB) Cancer–Chemotherapy I Title [DNLM: Neoplasms–drug therapy Antineoplastic Agents–therapeutic use QZ 267 A298c 2009] RC271.C5A35 2009 616.99’4061–dc22 2008052079 ISBN: 978-0-470-09254-5 (HB) ISBN: 978-0-470-09255-2 (PB) A catalogue record for this book is available from the British Library Set in 10.5/12.5 pt Times by Thomson Digital, Noida, India Printed and bound in Great Britain by Antony Rowe Ltd., Chippenham, Wiltshire First Impression 2009 Contents Preface ix Cancer epidemiology 1.1 Cancer incidence, prevalence and mortality 1.2 Childhood cancers 1.3 Global epidemiology 1 Histopathology of cancer 2.1 Introduction 2.2 Malignant, benign and normal (non-malignant) tissue 2.3 Cell death 11 11 11 12 Carcinogenesis, malignant transformation and progression 3.1 Introduction 3.2 Chemical carcinogenesis 19 19 19 Molecular biology of cancer: oncogenes and tumour suppressor genes 4.1 Introduction 4.2 Oncogenesis 4.3 Tumour suppressor genes 23 23 25 30 Tumour metastasis: a convergence of many theories 5.1 Introduction 5.2 Detachment and migration from the primary tumour 5.3 Intravasation 5.4 Transport 5.5 Extravasation 5.6 Growth of the metastatic tumour mass 37 37 37 38 42 43 45 vi CONTENTS Health professionals in the treatment of cancer 6.1 Introduction 6.2 Pathology 6.3 Radiology 6.4 Role of the surgical oncologist 6.5 Oncology pharmacy 6.6 Oncology nursing 6.7 The NHS Cancer Plan 49 49 49 50 51 52 53 54 Principles of cancer chemotherapy 7.1 Introduction 7.2 Timing of chemotherapy 7.3 Biomarkers and their uses 7.4 Clinical assessment of biomarkers 7.5 Pharmacogenetics and pharmacogenomics of cancer chemotherapy 55 55 55 59 59 64 Classical anticancer agents 8.1 Introduction 8.2 Alkylating agents 8.3 Antimetabolites 8.4 Agents derived from natural or semisynthetic products 8.5 Hormonal anticancer agents 8.6 Clinically used chemotherapy regimens 67 67 67 71 77 106 111 The philosophy of cancer research 9.1 Introduction 9.2 Structure of cancer research organizations in the United Kingdom 9.3 Cancer research in the United States 117 117 118 120 10 Novel anticancer agents 10.1 Introduction 10.2 Target validation 10.3 Identification and optimization of lead drugs 10.4 Preclinical pharmacology 125 125 125 146 148 11 Clinical trials 11.1 Introduction 11.2 Evaluation of treatment response 11.3 Assessment of vascularity and angiogenesis by nuclear medicine technology 167 167 169 173 CONTENTS vii 12 Tumour hypoxia 12.1 Introduction 12.2 Bioreductive drugs 12.3 Inhibitors of HIF-1 and HIF-1-regulated genes 177 177 181 187 13 Antiangiogenic and antivascular agents 13.1 History of angiogenesis as a therapeutic target 13.2 Anti-angiogenic drug targets 13.3 The return of thalidomide 13.4 Monoclonal antibodies as anti-angiogenic agents 13.5 The hollow fibre assay as a drug screen for anti-angiogenic drugs 13.6 Vascular disrupting agents 199 199 202 209 212 14 Tyrosine kinase inhibitors 14.1 Introduction 14.2 Tyrosine kinase inhibitors targeting angiogenesis 14.3 Non-receptor tyrosine kinase inhibitors 217 217 219 221 15 Ras inhibitors 225 16 Inhibitors of the Akt/PKB pathway 229 17 Targeting stress proteins: HSP90 inhibitors 233 18 The proteasome 18.1 Introduction 18.2 The proteasome as a target for novel drug strategies 18.3 Ubiquitylation as a target 237 237 239 240 19 Checkpoint protein kinases as novel targets – mammalian target of rapamycin (mTOR) 19.1 Mammalian target of rapamycin 19.2 Structure and activation of mTOR 19.3 Novel anticancer agents targeting mTOR 245 245 246 248 20 Telomerase 249 21 Histone deacetylase: an epigenetic drug target 21.1 Introduction 21.2 HDAC and DNA packaging 21.3 HDAC inhibitors 255 255 255 261 22 Pharmaceutical problems in cancer chemotherapy 22.1 Manifestation of toxicity 22.2 Regimen-related toxicity 265 265 269 213 215 viii CONTENTS 22.3 22.4 22.5 22.6 22.7 22.8 Secondary malignancies Drug resistance Pharmaceutical complications Phlebitis and venous irritation Health and safety National guidance on the safe administration of intrathecal chemotherapy 270 271 274 279 279 279 23 Oncology pharmacy at home and abroad 281 24 Practice exam questions 283 25 Bibliography and further reading 299 Index 331 Preface While researching this book, I came across a letter in the journal Nature asking for caution in the current trend for the use of humorous nomenclature for newly discovered genes1, the author referring to the tumour suppressor gene Pokemon, which I have briefly described in Chapter In this letter, the author reminded us that at a certain point, this name might have to be used by a health professional when discussing a clinical condition with a patient, a sobering thought that served as a reminder that every process started in the laboratory, however prolonged and seemingly removed from the clinic, potentially impacts on the lives of patients I decided to compile this book after being asked on a number of occasions by pharmacy students at the School of Pharmacy and Chemistry, Liverpool John Moores University if there were a book available that offered a concise, relatively inexpensive and broad introductory text that covered the content of my lecture course in cancer chemotherapy Specifically, their requests usually came following lectures describing the design, pharmacology and clinical development of novel anticancer agents for which there appeared to be only a limited range of reference sources suitable for undergraduates that didn’t involve lengthy searches through the scientific journals The research and treatment of cancer is a three-way collaboration between health professionals, clinical and experimental scientists, so I have tried to offer a text that unites the topics most pertinent to each group in order to foster a mutual understanding of the role of each at undergraduate level To this end, the book is aimed at undergraduates of pharmacy, medicine, dentistry, nursing and the allied health professions; as well as providing a useful primer for those considering a career in cancer research, whether they are undertaking a final year dissertation or graduate research project in this area I have attempted to summarize and consolidate the process behind the research and treatment of cancer, covering topics that range from the clinical aspects of cancer, such as its epidemiology and the role of the many of health professionals involved in its treatment, through to the currently accepted cancer chemotherapy regimens, in particular the classical cytotoxic anticancer agents Maclean, K (2006) Humour of gene names lost in translation to patients Nature, 439 (7074), 266 INDEX fadrazole 109 Fanconi anaemia (FA) 32, 34–5 farnesyl transferase 225–7 Fas ligand 15–16 Fas-associated death domain (FADD) 16 fertility problems 269 fibroblast growth factor (FGF) 47, 175 flavone acetic acid (FAA) 211, 215–16 flavopiridol 218–19 fludarabine 76, 78 fluorescence in situ hybridization (FISH) 130 fluorodeoxyglucose (FDG) 169–74 fluoromisonidazole 174, 184, 186 5-fluorouracil 76–7, 94 clinical regimens 113 pharmaceutical problems 265, 267, 278 pharmacogenetics 65 tumour hypoxia 186 flutamide 110–11, 115 focal adhesion kinase (FAK) 38 folate/folic acid 71–4 follicle-stimulating hormone (FSH) 110–11 formestane 109 free radicals 79, 82 fulvestrant 108–10 Fund for the Replacement of Animals in Medical Experiments (FRAME) 149 funding 117–18 fusion proteins 29–30 gain of function 132–5 Gardasil 26–7 gastrointestinal toxicity 267 gefitinib 137, 204, 218, 220–1 geldanamycin 234 gemcitabine 76, 78, 113 gender 1–3 gene targeted mice 150–7 genetic manipulation of cell lines 129–41 genetically engineered mouse models (GEMMs) 151–2, 154–61 genistein 219 genital warts 27–8 germ-line mutations 32 gimatecan 94, 97 glioblastoma 50 glucose transporter (Glut-1) angiogenesis 219 biomarkers 61 timing of chemotherapy 57 tumour hypoxia 183–4, 187, 191–6 335 glufosfamide 194 gonadotropin-releasing hormone (GnRH) 110–11 green card reporting 276–9 groove-binding agents 89–92 GTPase activating proteins (GAPs) 225 Gynecology Oncology Group (GOG) 281 H-ras 60 haematopoietic progenitor cells (HPCs) 48 health professionals 49–54 NHS cancer plan 54 oncology nurses 53–4 oncology pharmacists 52–3 pathologists 49–50 radiologists 50–1 surgical oncologists 51–2 heat shock proteins (HSPs) 233–6 Hematology Oncology Pharmacy Association (HOPA) 281 hepatic toxicity 267 HER2 oncogene angiogenesis 212 clinical trials 168 preclinical pharmacology 150–2, 154, 156–7 herceptin 137, 150, 168–9, 269 histone acetyl transferase (HAT) 255, 257 histone deacetylases (HDAC) 255–63 anticancer agents 257, 259–63 classification by isoform 258 DNA packaging 255–61 drug targets 257, 259–61 histopathology 11–18 apoptosis 12–17 autophagy 17 benign tissue 11–12 cell death 12–18 definitions 11–12 malignant tissue 11–12 necroptosis 17–18 necrosis 14–15 nomenclature 12–13 normal tissue 11–12 paroptosis 17 Hoescht 33, 342, 89–91 hollow fibre assays 213–15 hormonal anticancer agents 106–11, 115 hormone receptor negative tumours 56 hormone receptor positive tumours 56 HSP90 inhibitors 233–6 human papilloma virus (HPV) 26–8, 240 336 INDEX human telomerase reverse transcriptase (hTERT) 251 hydroximates 261–2 12-(S)-hydroxyeicosatetraenoic acids (HETE) 44 7-hydroxystaurosporine 188–9 hyperplasia 50 hypersensitivity 267, 269 hypoxia-inducible factor-1 (HIF-1) angiogenesis 201 biomarkers 61 checkpoint protein kinases 245–6 clinical trials 171 histone deacetylases 260 proteasome 241 target validation 137–8 tumour hypoxia 179–80, 183, 187–98 hypoxia-response element (HRE) 179, 191–2 ifosfamide 67 imatinib 30, 53, 218, 223 in vivo tumour models 148–57 indisulam 197 inducible gene expression systems 139–41 induction chemotherapy 56, 58 infertility 269 inflammatory diseases 202 inhalation chemotherapy 161, 164–5 insulin-like growth factor receptor (IGFIR) 17 integrin inhibitors 203–4, 209 intensification chemotherapy 58 intercalating agents 79, 81, 113–14 interferons (IFN) 115, 198, 210 interleukins (IL) 190, 198, 210 International Cancer Research Partners (ICRP) 119, 123 International Society for Oncology Pharmacy Practitioners (ISOPP) 281 intrathecal administration 279–80 intravasation 38–42 invadopodia 40–2 irinotecan 94, 96, 114 isoindolinones 241–3 isothiazolones 253–4 ixabepilone 104 K-ras 60 Kaplan–Meier plots 168–9 Kaposi’s sarcoma 83 Ki67 60 kidney see renal Knudson two-hit hypothesis 32 lactate dehydrogenase (LDH) 195 lapatinib 137, 220, 221 lead drugs 146–7 leflunomide 222 lenalidomide 210–12 lethal dose (LD) 167 letrozole 106, 108–9 leukaemias 3, 6, leutinizing hormone (LH) 110–11 Li–Fraumeni syndrome 32–3 lifestyle factors lipofection 135 liposomal doxorubicin 82–5 lomustine 67, 70 lonafarnib 226–8 loss of function 135 lox P gene 153 lung cancer 1, 9, 158, 162–5 lung cancer resistance protein (LRP) 271 lymph nodes 60 Macmillan Cancer Relief 54 macrophages 40–2 magnetic resonance imaging (MRI) 51, 55, 169–72 magnetic resonance spectroscopy (MRS) 172 maintenance chemotherapy 58 malignant melanoma 1, 10 progression 19–21, 26 tissue 11–12 mammalian mammary tumour virus (MMTV) 151, 154 mammalian target of rapamycin (mTOR) 229, 245–8 mammary intraepithelial neoplasia (MIN) 156 marimastat 204, 206 matrix metalloproteinase (MMP) inhibitors 203–9 matrix metalloproteinases 39–40, 86–7 maximum tolerated dose (MTD) 167 MDM2 oncogene 31, 35, 241–3 melaphalan 67, 70, 112, 269 menopause 2, 56, 108 6-mercaptopurine 74–5 mesenchymal tissue 13 messenger RNA (mRNA) 142 INDEX metaphase chromosome 249–50 metastasis 37–48 angiogenesis 43 cancer dormancy 45 detachment and migration 37–8, 39 endothelial retraction 44 extracellular matrix 37–8, 45–6 extravasation 41, 43–4 growth of tumour mass 45–8 intravasation 38–42 pathology 50 seed and soil hypothesis 46–8 timing of chemotherapy 55–7 transport of tumour cells 42–3 metastat 204, 207–8 methotrexate 65, 71–4, 113, 265, 267 metronidazole 181, 184 MIAME VICE 142–3 microarrays 129–32, 141–3 microcarrier beads 144–5 microtubules 96, 100–4 miletaxel 103 misonidazole 181–2, 184 mithramycin 92–3 mitomycin 87–9, 182, 184, 186 mitotic inhibitors 95–105 molecular biology of cancer 23–35 altered products 28–30 amplification of normal gene products 26, 28 cancer susceptibility syndromes 32–5 cell cycle 23–5 chromosomal rearrangements 29–30 Knudson two-hit hypothesis 32 oncogenesis 23, 25–30 tumour suppressor genes 23, 26–8, 30–5 molecular genetics 141–3 monocarboxylate transporters (MCTs) 195–6 monoclonal antibodies 212–13, 221 MRC clinical trials 119–20 MTIC 67–8, 71 MTT assays 147 mucous membrane toxicity 265 multidrug resistance 62, 65, 178, 195, 271 multidrug resistance protein (MRP) 219, 271 multiple myeloma 209 mustine 67 MYCN 61 N-ras 60 naltrindole 230 337 National Cancer Institute (NCI) angiogenesis 213 lead drugs 146 pharmaceutical problems 265–6 preclinical pharmacology 150, 161 research philosophy 119–21, 123 target validation 128–9, 131–2, 142 tumour hypoxia 190 National Cancer Research Institute (NCRI) 54, 118–20, 123 National Cancer Research Network (NCRN) 120, 148 National Extravasation Information Service 276–9 National Institute for Clinical Excellence (NICE) 54, 68 National Institutes of Health (NIH) 119 natural killer (NK) cells 210 necroptosis 17–18 necrosis 14–15, 23 necrostatin-1 17 nelarabine 77–8 nemorubicin 80 neoadjuvant chemotherapy 58 neoplasms 11 neovastat 204, 207 neuroblastoma neuroectodermal tissue 13 neurotoxicity 267 NHS cancer plan 54 nilotinib 221, 223 nilutamide 110–11 nitrogen oxide synthase (NOS) 186 2-nitroimidazoles 61, 181–2, 184 non-epithelial mesenchymal tissue 13 non-Hodgkin lymphoma (NHL) 2, 4, non-receptor tyrosine kinase inhibitors 218, 221–3 non-small cell lung cancer (NSCLC) 57, 158 normal tissue 11–12 Northern blotting 142 nuclear factor (NFB) angiogenesis 210, 216 cell death 17–18 proteasome 237–9 tumour hypoxia 188–90 nuclear medicine 173–5 nucleoside analogues 76–7 nutlins 241–2 338 INDEX oesophageal cancer 1–2 oestrogen antagonists 107–8 anticancer agents 106–7 receptors 47–8 Okazaki fragments 249–50 oncogenesis 23, 25–30 proto-oncogenes 25, 28–30 viral 25–8 oncology nurses 53–4 pharmacy 52–3, 281–2 surgical 51–2 ONCOMINE 142 oncosis 14 oral cancer oral squamous cell carcinoma 57 osteogenesis 202 osteosarcomas 161, 163–4 ovarian ablation 56 ovarian cancer 158 oxaliplatin 67, 70 oxygen degradation domain (ODD) 246 oxygen-dependent degradation (ODD) 137–8 p-glycoprotein inhibitors 219, 271–2 p53 gene biomarkers 60 oncogenesis 26–8 proteasome 237, 240–3 target validation 137 tumour suppressor genes 30–1, 35 paclitaxel biomarkers 65 clinical regimens 114 clinical trials 168 Ras inhibitors 227–8 toxicity 266–7 tumour hypoxia 193 pancreatic cancer epidemiology preclinical pharmacology 159 panitumumab 213 parathyroid hormone-related protein (PTHrP) 47 paroptosis 17 pathologists 49–50 pazopanib 222 PD-ECGF 62 pemetrexed 65, 71–2 perfusion-limited hypoxia 177–8 perifosine 230 pharmaceutical problems 265–80 alteration of drug targets 274 complications 274–9 drug resistance 62, 65, 178, 195, 271–4 enhanced DNA repair 271–4 extravasation 275–9 green card reporting 276–9 health and safety measures 279–80 intrathecal administration 279–80 phlebitis 279 regimen-related toxicity 269–70 risk factors 268–9 secondary malignancies 270–1 toxicity 265–70 venous irritation 279 Philadelphia chromosome 29–30 phlebitis 279 pimonidazole 182 plasmids 132–5 platelet-derived growth factor (PDGF) 48 platelet-derived growth factor receptor (PDGFR) 217, 220, 222 podosomes 40–2 poly (ADP-ribose) polymerase (PARP) enzymes 273–4 polymerase chain reaction (PCR) 129 porfiromycin 182 positron emission tomography (PET) 51, 55, 169–74 preclinical pharmacology 148–65 comparative oncology 157–65 in vivo tumour models 148–57 transgenic/gene targeted mice 150–7 tumour xenografts 149–50 prinomastat 204, 206–7 procarcinogens 19–20 prodrugs 67, 71, 85–7 prostate cancer 1, 3, 158 prostate-specific antigen (PSA) 3, 47, 59, 63 proteasome 237–43 drug targets 239–40 ubiquitylation as target 240–3 protein kinase B 229–31 protein kinase C inhibitors 188–9 proto-oncogenes 25, 28–30 purine analogues 74–6 purine inhibitors 71–4 PyMT gene 151, 155–6 pyrimidine analogues 76 pyrimidine inhibitors 71–4 INDEX quercetin 218–19 radiologists 50–1 raloxifene 109 raltitrexed 71–2 ranibizumab 213 rapamycin 245–8 Ras inhibitors 225–8 reactive oxygen species (ROS) 16 reciprocal recombination 153 regimen-related toxicity 269–70 remission 55–6 renal cancer 1–2 renal toxicity 267 rencarex 198 research philosophy 117–23 basic research 117–18 funding 117–18 translational research 117–18 United Kingdom 118–20 United States 120–3 restriction enzymes 134 retinoblastomas 3–4 reverse transcriptase-PCR-based assays 142 rhabdomyosarcoma rhodacyanines 253–4 RING domains 240–1 RIP kinase 17–18 RNA induced silencing complex (RISC) 136–7 RNA interference (RNAi) 135–7 RNA viruses 25, 26 rTA protein 139–40 runt-related transcription factor (RUNX2) 47 S-nitroso-N-acetyl-penicillamine (SNAP) 193–4 sabarubicin 80, 81 salvage chemotherapy 58 sarcoma 12 scaffold proteins 144–5, 256 screening in vitro 147 secondary malignancies 270–1 seed and soil hypothesis 46–8 selective oestrogen receptor modulating agents (SERMs) 56, 107–8 semustine 67 SF2 62 shepherdin 235–6 339 short hairpin RNA (shRNA) 136–7 small cell lung carcinoma 158 small interfering RNA (siRNA) 136 smear tests 52 somatic mutations 32 sorafenib 220, 222 squamous cell carcinoma 12 squamous intraepithelial lesions (SIL) 27 Src kinases 217–18, 221–3 staging 50, 52, 56–7 standard uptake values (SUVs) 171, 173–4 STEALTH liposomes 83, 85, 161 stress proteins 233–6 sunitinib 220, 222 surgical oncologists 51–2 survivin 236 T-cells 77 tallimustine 93 tamoxifen 56, 107–9, 115 tanespimycin (17-AAG) 234–6 tanomastat 204, 207 target validation 125–46 dominant negative genes 137–9 extracellular matrix gels 145–6 gain of function/upregulation of expression 132–5 genetic manipulation of cell lines 129–41 inducible gene expression systems 139–41 loss of function/downregulation of expression 135 microarrays 129–32, 141–3 microcarrier beads 144–5 molecular genetics 141–3 RNA interference 135–7 role determination in vitro 127–9 scaffolds 144–5 three-dimensional in vitro models 143–6 tumour cell spheroids 144–5 taxanes 101–4 telomerase 61, 249–54 telomerase repeat amplification protocol (TRAP) 251–2 temozolomide 67–8, 71, 274 temsirolimus 247–8 teniposide 97 testicular cancer tetracyclines 139–41, 207–8 thalidomide 204, 209–12 therapy-related leukaemia (TRL) 270 340 INDEX 6-thiopurines 74–6 thiotepa 67, 70 three-dimensional in vitro models 143–6 thrombospondin-1 45 thymidylate synthase 65 timing of chemotherapy 55–9 tipifarnib 226–8 tirapazamine 65, 182, 185–7 tissue array research programme (TARP) 122, 129, 131–2 tissue inhibitors of matrix metalloproteinase (TIMPS) 205 tissue microarrays see microarrays TNF-related apoptosis inducing ligand (TRAIL) 15–16, 31, 210, 229 topoisomerase inhibitors 92–5, 97 topoisomerases 79, 84, 92–5 topotecan 94, 96, 188 toremifene 109 toxicity 131, 167, 265–70 trabectidin 89–91 transduction 134–5 transfection 135 transformation 132, 134 transforming growth factors (TGF) 210 transgenic/gene targeted mice 150–7 transitions 19–20 translational research 117–18 transport of tumour cells 42–3 transversions 19–20 trastuzumab 137, 150, 168–9, 212, 269 treatment response 167–73 trichostatin A 261–2 triethylenemelamine 67, 70 tubulins 96, 99–101, 103–4 tumour angiogenesis factor (TAF) 200–1 tumour cell spheroids 144–5, 181 tumour hypoxia 177–98 biomarkers 57, 61 bioreductive drugs 181–7 chronic/acute 177–8, 181 HIF-1 inhibitors/HIF-1 regulated genes 187–98 multidrug resistance 178, 195 tumour metastasis see metastasis tumour necrosis factor (TNF) angiogenesis 210, 216 histone deacetylases 260 receptors 15 tumour hypoxia 190 tumour suppressor genes 23, 30–5 cancer susceptibility syndromes 32–5 Knudson two-hit hypothesis 32 p53 gene 26–8, 30–1, 35 tumour xenograft models angiogenesis 199–200 preclinical pharmacology 149–50 tumour hypoxia 181, 187, 193–4 tumour/node/metastasis (TNM) system 155 tumstatin 203–5 tyrosine kinase inhibitors 217–23 angiogenesis 219–21 non-receptor 218, 221–3 ubiquitins 233–4, 237–8, 240–3 UK Clinical Research Collaboration (UKCRC) 117–18 ultimate carcinogens 19–20 upregulation of expression 132–5 uracil 76 usual ductal hyperplasia (UDH) 156 uterine cancer, epidemiology valproic acid 261–3 valspodar 271–2 vandetanib 222 vascular endothelial growth factor (VEGF) angiogenesis 202–4, 210, 212–13 biomarkers 62 clinical trials 170, 173, 175 histone deacetylases 260 metastasis 42–5, 47–8 tumour hypoxia 179–80, 188 tumour suppressor genes 32 tyrosine kinase inhibitors 217, 220, 222 vascular permeability factor (VPF) 44 vascularity 62, 173–5 anticancer agents 199–200, 214–16 see also angiogenesis; tumour hypoxia vatalanib 222 venous irritation 279 verapamil 272 Veterinary Cancer Register 157 vinblastine 100–2 vinca alkaloids 100–2 vincristine 65, 100–2, 114, 267, 279–80 vindesine 100–2 vinflunine 101–2 vinorelbine 102 viral oncogenesis 25–8 virus-like particles (VLPs) 27 341 INDEX vitaxin 175, 191, 204, 209 volociximab 204, 209 von Hippel–Lindau disease 32, 34 vorinostat 255, 261–3 World Health Organization (WHO) 265 wortmannin 230 Wales Cancer Bank 120 Warburg effect 169, 191 zidovudine 252–3 zygote injection 150–1 xeroderma pigmentosum (XP) 32, 34–5 Map Summary of cellular and molecular events controlling tumour metastasis Figure 6.1 Pathology of glioblastoma: typical pathology shows a gradation between normal tissue, infiltrating border zones of hyperplasia and tumour tissue These samples have been immunohistochemically stained for facilitative glucose transporter Glut-1 (brown) Reproduced with permission from an original photograph by Natalie Charnley, Academic Department of Radiation Oncology, University of Manchester Figure 7.1 Facilitative glucose transporter Glut-1 expression (brown staining) detected by immunohistochemistry in samples of oral squamous cell carcinoma surgically removed from a patient The highest level of expression was found in (a) invading tumour tissue (arrows) or (b) around necrosis, indicating a biological link with malignancy and hypoxia Accordingly, Glut-1 may be used as a marker of malignancy, hypoxia and prognosis in a range of solid tumour types Reproduced from Oliver et al (2004) Eur J Cancer, 40, 503–7 Figure 10.4 Tissue microarrays obtained from the National Cancer Institute TARP laboratory (a), consisting of cores of tumour samples taken from human patients, covering a range of tumour types including breast, colon, renal, central nervous system, ovarian, lung, skin, prostate and leukaemia (b) (c) basic immunohistochemistry was carried out to determine the variation of facilitative glucose transporter Glut-1 expression between normal tissue and across the different tumour types The circular structures are tissue cores highlighted here by the blue haematoxylin counterstain, which stains cellular components such as nuclei and plasma membranes and provides structural context for immunohistochemical staining when observed by light microscopy Figure 10.5 Microarrays may also be prepared using cores of agarose embedded pellets of formalin-fixed cell cultures Pictured here are microarrays obtained from the National Cancer Institute TARP laboratory carrying the NCI-60 panel of tumour cell lines These were stained for Glut-1 using immunohistochemistry and placed under Â400 magnification The extent of Glut-1 expression was graded according to the area and intensity of staining (BT549 ¼ 0; MCF7 ¼ 1, OVCAR ¼ 2; HCC2998 ¼ 3, IGROV1 ¼ 4; SNB19 ¼ 5) Reproduced from Evans et al (2007) Cancer Chemother Pharmacol., Springer SWIN|xancPOi25B1CkpP2ICoeVw==|1251295657 Figure 11.4 DCE-MRI images in a patient with liver metastasis from cholangiocarcinoma taking part in a phase I trial of BMS-582 664, a novel VEGFR/FGFR tyrosine kinase inhibitor Posttreatment images demonstrate complete absence of contrast agent uptake into this tumor The subject subsequently had a confirmed partial response by CT scan Reproduced from Galbraith (2006) NMR Biomed 19: 681–689, John Wiley & Sons Inc Figure 11.5 DCE-MRI image of a breast tumour in a patient taking part in a study aimed at evaluating MRI as a means of predicting histological response to primary chemotherapy (PCT) These images, showing two characteristic patterns, homogeneous (a) and ring like (b), were taken to provide baseline contrast enhancement values as a measure of tumour volume before treatment Reproduced from Martincich et al (2004) Br Cancer Res Treat 83: 67–76, Springer Figure 12.3 Chronic hypoxia modelled in tumour xenografts and tumour cell spheroids Figure 13.12 The hollow fibre assay for preclinical evaluation of anti-angiogenic agents Map The discovery, optimisation and clinical development of novel anticancer agents .. .Cancer Chemotherapy Rachel Airley Cancer Research Scientist and Lecturer in Pharmacology Cancer Chemotherapy Cancer Chemotherapy Rachel Airley Cancer Research Scientist and Lecturer in Pharmacology. .. breast (77%) and cervix (61%) cancers; 10–50% survival, including colon (47% in males, 48% in females), renal (45% in males, 48% in females) and brain (12% in males, 15% in females); and cancers where... Vascular disrupting agents 199 199 202 209 212 14 Tyrosine kinase inhibitors 14.1 Introduction 14.2 Tyrosine kinase inhibitors targeting angiogenesis 14.3 Non-receptor tyrosine kinase inhibitors 217