1 Cancer Biotherapy:Progress in China&Zhen-Yu Ding and Yu-Quan Wei 1
1.1 Introduction 1
1.2 Immunotherapy 2
1.2.1 Cancer Vaccine 2
1.2.2 Cell Therapy 3
1.2.3 Antibody Therapy 8
1.3 Gene Therapy 11
1.4 Antiangiogenesis Therapy 19
1.5 Targeted Therapy 21
2 Cancer Targeting Gene-Viro-Therapy and Its Promising Future&Xin-Yuan Liu,Wen-Lin Huang,Qi-Jun Qian,Wei-Guo Zou,Zi-Lai Zhang,Liang Chu,Kang-Jian Zhang,Li-Li Zhao,Yan-Hong Zhang,Song-Bo Qiu,Zhen-Wei Zhang,Tian Xiao,Jun-Kai Fan,Na Wei,Xin-Ran Liu,Xin Cao,Jin-Fa Gu,Rui-Cheng Wei,Miao Ding,and Shuai Wu 33
2.1 Gene Therapy of Cancer 34
2.1.1 Introduction 34
2.2 Replicating Oncolytic Virus on Cancer Therapy 45
2.3 Cancer Targeting Gene-Viro-Therapy(CTGVT) 47
2.3.1 General Description of CTGVT 47
2.4 Modification of CTGVT 55
2.4.1 Cancer Targeting Dual Gene-Viro-Therapy 55
2.4.2 CTGVT with RNAi 63
2.4.3 CTGVT by Killing CSC 64
2.4.4 CTGVT for Tissue-Specific Cancer 67
2.4.5 CTGVT with Cytokine Armed Antibodies 68
2.5 Questions 71
2.6 Conclusion 73
3 Relationship Between Antiproliferative Activities and Class I MHC Surface Expression of Mouse Interferon Proteins on B16-F10 Melanoma Cells&Ronald G.Jubin,Doranelly H.Koltchev,Diane Vy,and Sidney Pestka 85
3.1 Introduction 85
3.2 Materials and Methods 87
3.2.1 AP Assay 87
3.2.2 MHC I Up-Regulation 87
3.3 Results 88
3.3.1 AP Activity 88
3.3.2 MHC I Surface Expression 90
3.4 Discussion 91
4 Mitotic Regulator Hec1 as a Potential Target for Cancer Therapy&Erin M.Goldblatt,Eva Lee and Wen-Hwa Lee 97
4.1 Cell Growth and Cancer 98
4.2 Mitotic Regulators as Cancer Therapy Targets 101
4.3 Discovery of Hec1,a Novel Protein in Mitotic Regulation 103
4.4 Development of Hec1 Inhibitors for Cancer Therapeutics 106
4.5 Conclusion 109
5 Advances in Liposome-Based Targeted Gene Therapy of Cancer&Jennifer L.Hsu,Chi-Hong Chao,Xiaoming Xie,and Mien-Chie Hung 113
5.1 Introduction 113
5.2 Cationic Liposome-Mediated Nonviral Gene Delivery 114
5.3 Improvement of Therapeutic Efficiency of Liposome-Mediated Gene Therapy 115
5.3.1 Modifications of Liposome Composition 115
5.3.2 Combinational Strategy for Liposome-Mediated Gene Therapy 116
5.4 Improvement of Nonviral Gene Expression System 117
5.4.1 Cancer/Tissue-Specific Promoters 117
5.4.2 Two-Step Transcription Amplifier Module 120
5.4.3 VISA Expression Platform 120
5.5 Therapeutic Genes for Cancer Gene Therapy 121
5.5.1 p53 121
5.5.2 E1A 122
5.5.3 Bik 123
5.5.4 HSV-TK 124
5.6 Conclusion 124
6 Rewiring the Intracellular Signaling Network in Cancer&Jing Liu and Anning Lin 135
6.1 Introduction 135
6.2 The JNK Signaling Pathway 136
6.3 The NF-κB Signaling Pathway 136
6.4 The Negative Crosstalk Between NF-κB and JNK1 Wires the TNF-α Signaling Circuitry for Cell Survival 137
6.4.1 The TNF-α Signaling Circuitry and Cell Death 137
6.4.2 The Crosstalk Between NF-κB and JNK Determines TNF-α Cytotoxicity 138
6.4.3 Multiple Mechanisms Are Involved in NF-κB-Mediated Inhibition of TNF-α-Induced Prolonged JNK Activation 139
6.4.4 Prolonged JNK1 Activation Contributes to TNF-α-Induced Cell Death Through Elimination of Caspase Inhibitor(S) 141
6.5 The Positive Crosstalk Between NF-κB and JNK1 Wires the UV Signaling Circuitry for Cell Death 142
6.5.1 The UV Signaling Circuitry and Cell Death 142
6.5.2 Augmentation of UV-Induced Rapid and Robust JNK Activation by NF-κB Promotes UV-Induced Cell Death 142
6.5.3 The"Priming"Model in Which the Preexisting Nuclear RelA/NF-κB via Induction of PKCδ to Promote UV-Induced Cell Death 143
6.5.4 The RelA-PKCδ Axis May Be Involved in the Assembly of UV-Induced JNK1 Signalsome 143
6.5.5 JNK1 Contributes to UV-Induced Cell Death Through Promotion of both Cytoplasmic and Nuclear Death Events 144
6.6 Toward Cell Signaling-Based Cancer Therapy 145
7 Research and Development of Highly Potent Antibody-Based Drug Conjugates and Fusion Proteins for Cancer Therapy&Rong-guang Shao and Yong-su Zhen 153
7.1 Introduction 153
7.2 Intact AbDCs 154
7.2.1 mAb-Maytansinoid Drugs 155
7.2.2 mAb-Auristatin Drugs 159
7.2.3 mAb-Enediyne Drugs 161
7.3 Downsizing ADCs 163
7.3.1 Fragment mAb-Drug Conjugates 164
7.3.2 Engineered Antibody-Based Fusion Proteins 165
7.4 Conclusion 167
8 Cancer Stem Cell&Qiang Liu,Feng-Yan Yu,Wei Tang,Shi-Cheng Su,and Er-Wei Song 173
8.1 Introduction 173
8.2 History of CSC 175
8.3 Controversy Over CSC 177
8.4 Origin of CSC 178
8.5 Pivotal Signaling Pathways in CSCs 180
8.5.1 Wnt Pathway 181
8.5.2 Hedgehog Pathway 181
8.5.3 Notch Pathway 182
8.5.4 Pathways Related with Cancer Therapy 182
8.5.5 Other Pathways 183
8.6 CSCs and Metastasis 184
8.6.1 Phenotype of CSCs Related to Metastasis 184
8.6.2 Mechanism of Cancer Metastasis Regulated by Niche 184
8.6.3 CSC and EMT 185
8.6.4 CSC and Angiogenesis 185
8.6.5 Anoikis and Circulating Tumor Cells 186
8.7 Cancer Therapies Targeting CSCs 186
8.7.1 Targeting the Self-Renewal Ability 187
8.7.2 Targeting Survival Pathways 187
8.7.3 Targeting ABC Transporters 188
8.7.4 Targeting Cell Surface Marker and the Interaction with Niche 188
8.8 Future Directions of CSC 188
9 p53:A Target and a Biomarker of Cancer Therapy?&Xin Lu 197
9.1 Introduction 197
9.2 Can p53 Act as a Biomarker in Cancer Management and Therapy? 200
9.2.1 p53 Mutation Status and Cancer Management 200
9.2.2 Clinical Implications of Serological Analysis of Auto-Anti-p53 Antibodies 202
9.3 p53-Based Cancer Therapy 203
9.3.1 Increasing Wild-Type p53-Mediated Killing 203
9.3.2 Utilizing Mutant p53 to Induce Cancer Cell Death 204
9.4 What Can We Do to Accelerate p53-Based Cancer Management and Therapy? 207
10 Recombinant Adenoviral-p53 Agent(Gendicine？):Quality Control,Mechanism of Action,and Its Use for Treatment of Malignant Tumors&Shu-Yuan Zhang,You-Yong Lu,and Zhao-Hui Peng 215
10.1 Introduction 215
10.2 Recombinant Adenoviral-p53 Agent(Trademarked Gendicine) 218
10.2.1 Product Description 218
10.2.2 Quality Control 219
10.3 Mechanisms of Actions 220
10.4 Safety of Gendicine in Clinics 223
10.5 Efficacy of Gendicine in Clinics 224
10.5.1 Gendicine in Combination with Radiation Therapy for Treatment of Nasopharyngeal Carcinoma and HNSCC 224
10.5.2 Gendicine in Combination with Chemotherapy for Treatment of Advanced Cancers 226
10.5.3 Gendicine in Combination with Hyperthermia for Treatment of Advanced Cancers 232
10.6 Overview of Intellectual Property Rights of Recombinant Ad-p53,Methods of Manufacture,and Clinical Applications 233
10.6.1 Four Core Patents Covering Recombinant Ad-p53 Compositions 233
10.6.2 Two Patents for Methods of Recombinant Ad-p53 Manufacture 235
10.6.3 Two Patented Cell Lines for Production of Recombinant Adenoviral Vectors 235
10.6.4 Patents Covering Clinical Use of Recombinant Ad-p53 236
10.7 Summary and Prospective 237
11 Three-Dimensional Tumor Model and T-Lymphocytes Immunotherapy for Cancer&Hua Liu 245
11.1 Introduction 245
11.2 Three-Dimensional Tumor Models 246
11.2.1 Anticancer Drug Discovery 250
11.2.2 In Vitro Drug Resistance Test 251
11.2.3 Metastasis Tumor 252
11.2.4 Cancer Stem Cells 252
11.3 3D Tumor Model and T-Lymphocytes Immune Therapy for Cancer 253
11.3.1 New Dimension of Immune Therapy 253
11.3.2 Activation of Immune Cells(Initial Stage) 255
11.3.3 Proliferation of the Effectors(Induced Stage) 256
11.3.4 Biologic Effects Against Tumor(Effective Stage) 256
11.3.5 Clinical Observation 258
11.4 Recent Advances in Cancer Immune Therapy 258
11.4.1 The Tumor Antigens 258
11.4.2 The Immune Effectors 259
11.4.3 The Host Environment 263
11.5 New Strategies for Cancer Therapy Based on Immune Intervention 266
11.5.1 Synergy and Individualized Cancer Treatments 266
11.5.2 Combinatorial Immunotherapy for Cancer 276
11.6 Conclusion 281
12 Advances in Cancer Chemotherapeutic Drug Research in China&Bin Xu,Jian Ding,Kai-Xian Chen,Ze-Hong Miao,He Huang,Hong Liu,and Xiao-Min Luo 287
12.1 Introduction of Background of Anticancer Drug Research in China 287
12.2 Natural-Derived Anticancer Agents Developed in China 290
12.2.1 Gengshengmeisu(Actinomycin K,D) 290
12.2.2 Hydroxycamptothecin 292
12.2.3 Homoharringtonine 292
12.2.4 Polysaccharide Preparations 293
12.2.5 Some Meaningful Anticancer Substances from Traditional Chinese Medicine(TCM) 293
12.3 Synthetic Anticancer Drugs 294
12.3.1 Alkylating Agents 294
12.3.2 Metal Anticancer Agents,Antimony-71(Sb-71),Sb-57,and so forth 298
12.3.3 Other Effective Compounds and Preparations 299
12.4 New Inhibitors of Topoisomerases and Molecular-Targeted Anticancer Agents 300
12.4.1 New Inhibitors of Topoisomerases 300
12.4.2 Molecular-Targeted Anticancer Agents 311
12.5 Recent Work on Design,Synthesis,and Antitumor Evaluation of Several Series of Derivatives 317
12.5.1 N-Substituted-Thiourea Derivatives 317
12.5.2 3,5-Substituted Indolin-2-One Derivatives 321
12.5.3 3-Nitroquinolines 325
12.5.4 Quercetin-3-O-Amino Acid-Esters 328
12.5.5 Triaminotriazine Derivatives 332
12.6 Discussion and Perspectives 338
13 Doxorubicin Cardiotoxicity Revisited:ROS Versus Top2&Yi Lisa Lyu and Leroy F.Liu 351
13.1 Doxorubicin Kills Tumor Cells Through Top2 Poisoning 351
13.2 Doxorubicin Causes Unique Tissue Toxicities 355
13.3 Doxorubicin Cardiotoxicity,an ROS Theory 355
13.4 Doxorubicin Cardiotoxicity,a Top2 Twist 356
13.5 Prevention of Doxorubicin Cardiotoxicity by ICRF-187 357
13.5.1 Antagonizing the Formation of Doxorubicin-Induced Top2-DNA Covalent Adducts 359
13.5.2 Top2β Depletion Through Proteasome-Mediated Degradation 360
13.6 Conclusion 360
14 Biochemistry and Pharmacology of Human ABCC1/MRP1 and Its Role in Detoxification and in Multidrug Resistance of Cancer Chemotherapy&Wei Mo,Jing-Yuan Liu,and Jian-Ting Zhang 371
14.1 Introduction 371
14.2 Structure of ABCC1 372
14.3 Monomer Versus Dimer 376
14.4 Regulations of ABCC1 Expression 377
14.5 Biogenesis and Trafficking 378
14.6 Mechanism of Action 380
14.7 Substrates of ABCC1 384
14.8 Inhibitors of ABCC1 386
14.9 Physiologic Functions of ABCC1 389
14.10 ABCC1 in Clinical Drug Resistance 390
14.11 Conclusion and Perspectives 391
15 The Role of Traditional Chinese Medicine in Clinical Oncology&Yan Sun and Jing-Yu Huang 405
15.1 Historical Note on the Understanding of Cancer:West and East 405
15.2 Search for Anticancer Agents from Medicinal Plants 407
15.3 Traditional Medicinal Herbs as BRMs 409
15.3.1 Results of Clinical Trials 409
15.3.2 Experimental Studies 412
15.3.3 Long-Term Follow-Up 415
15.4 TCM as Angiogenesis Inhibitors 416
15.4.1 Studies in Esophageal Cancer 416
15.4.2 In Nonsmall Cell Lung Cancer 423
15.4.3 Other TCM Herbs 424
15.5 Future Perspective-Integration of TCM with Modern Medicine Both in Experimental and in Clinical Study 425
16 Effect of Arsenic Trioxide on Acute Promyelocytic Leukemia and Glioma:Experimental Studies,Clinical Applications,and Perspectives&Shi-Guang Zhao,Jin Zhou,Yao-Hua Liu,Li-Gang Wang,and Bao-Feng Yang 431
16.1 Historical Perspectives of Arsenic Derivatives in Medicine 431
16.2 Effect of Arsenic Trioxide in APL 432
16.2.1 What Is the Role of Arsenic in Newly Diagnosed APL? 432
16.2.2 Conclusion and Perspectives:Can We Induce a 100R Rate in Newly Diagnosed APL? 434
16.3 The Application of Arsenic Trioxide in Glioma 434
16.3.1 Characteristics of Glioma 434
16.3.2 Experimental Studies 437
16.3.3 Clinical Application 441
16.3.4 Perspectives 445
16.4 Experimental Studies and Clinical Applications of As2O3 in Harbin Medical University 447
16.5 Conclusions 447
17 Recent Advances in Nasopharyngeal Carcinoma Research and Its Pathogenesis&Yi-Xin Zeng,Wenlin Huang,and Kai-tai Yao 453
17.1 Introduction 453
17.2 Molecular Pathogenesis of NPC 454
17.2.1 Genetic Factor and NPC Susceptibility 454
17.2.2 EBV and NPC 457
17.3 Molecular Diagnosis of NPC 462
17.3.1 Discovery of Molecular Biomarker of NPC 462
17.3.2 Application of Molecular Diagnosis in NPC 466
17.4 Advances in the Treatment of NPC 469
17.4.1 Clinical Application of Cytotoxic Therapeutics 469
17.4.2 Targeted Therapy 470
17.4.3 Immunotherapy 472
17.4.4 Gene Therapy 474
17.5 Summary 479
18 Esophageal Carcinoma&Qi-min Zhan,Lu-hua Wang,Yong-mei Song,Yun-wei Ou,Jing Jiang,Jing Fan,Jing-bo Wang,and Jie Shen 493
18.1 An Overview of Esophageal Carcinoma 493
18.1.1 Epidemiology 494
18.2 The Pathogenesis of Esophageal Carcinoma 496
18.2.1 The Pathogenesis of Barrett's Esophagus 496
18.2.2 The Pathogenesis of Esophageal Carcinoma 497
18.3 The Etiopathogenesis of Esophageal Carcinoma 503
18.3.1 Diet,Smoking,and Intemperance 503
18.3.2 Genetics and Genes 503
18.3.3 Virus and Inflammation 504
18.4 The Treatment of Esophageal Carcinoma 504
18.4.1 Anatomy 504
18.4.2 Histology 504
18.4.3 Clinical Presentation 505
18.4.4 Diagnostic Work-Up 505
18.4.5 Stage 506
18.4.6 Treatment 507
18.5 The Prevention of Esophageal Carcinomas 521
18.5.1 Protecting the Esophagus by Changing Poor Diet and Living Habits 521
18.5.2 Reducing the Intake of Nitrosamines 522
18.5.3 The Significance of Balanced Nutrition 523
18.5.4 The Active Treatment of Esophageal Epithelial Hyperplasia and Severe Esophagitis 524
18.5.5 The Identification of the Genetic Susceptibility to Esophageal Cancer Among Groups or Individuals 524
19 Research on Colorectal Cancer in China&Shu Zheng,Su-Zhan Zhang,Kun Chen,Yong-Liang Zhu,and Qi Dong 535
19.1 The Progress of Epidemiological Study on CRC 535
19.1.1 Introduction 535
19.1.2 Distribution of CRC 536
19.1.3 Environmental Influencing Factors 539
19.1.4 Physical Activity and Obesity 541
19.1.5 Medical History 541
19.1.6 Family History of Cancer 542
19.1.7 Biomarkers 542
19.1.8 Genome Wide Association Study 545
19.1.9 Conclusions 546
19.2 CRC Screening and Early Detection in China 547
19.2.1 Introduction 547
19.2.2 The First Population-Based CRC Screening and Prospective Cohort Study in Haining County 547
19.2.3 Cluster Randomization Trial of Sequence Mass Screening for CRC in Jiashan County 551
19.2.4 Validity of Immunochemical Fecal Occult Blood Test and High-Risk Questionnaire in a Population-Based CRC Screening in Hangzhou 554
19.2.5 Conclusion 555
19.3 The Clue of Microbe Pathogens and CRC—Study on the Carcinogenesis of Microcystin and H.pylori 556
19.3.1 Introduction 556
19.3.2 Epidemiology Survey of Microcystin and H.pylori Prevalence 557
19.3.3 Experimental Study of Molecular Carcinogenesis of Microcystin and H.pylori Molecular Carcinogenesis of Microcystin 558
19.3.4 Molecular Carcinogenesis of H.pylori 561
19.3.5 Activation of Erk1/2 Pathway Was Involved in Carcinogenesis 563
19.3.6 Conclusion 566
19.4 CRC-Related Gene(SNC6/ST13,SNC19/ST14,SNC73) 567
19.4.1 Introduction 567
19.4.2 SNC6/ST13 569
19.4.3 SNC19/ST14 573
19.4.4 SNC73 582
20 Molecular and Cellular Characteristics of Small Cell Lung Cancer:Implications for Molecular-Targeted Cancer Therapy&Yu-Juan Jin,Chao Zheng,and Hong-Bin Ji 597
20.1 Introduction 597
20.2 Clinical Diagnosis and Staging of SCLC 598
20.3 The Clinical Management of SCLC 599
20.4 Genetic Alteration of SCLC 600
20.4.1 Oncogenes 600
20.4.2 Allelic Loss of Chromosome in SCLC 601
20.4.3 Dys-regulation of Signaling Pathways in SCLC 603
20.5 Transition from SCLC to Its Variants and/or NSCLC 606
20.6 SCLC Metastasis 607
20.7 Drug Resistance of SCLC 608
20.8 Perspective 609
21 Possibility to Partly Win the War Against Cancer&Xin-Yuan Liu,Guang-Wen Wei,Dong-Qin Yang,Lun-Xu Liu,Lin Ma,Xiao Li,Jian OuYang,Cui-Ping Li,Kang-Jian Zhang,Jian Wang,Liang Chu,Jin-Fa Gu,Huang-Guang Li,Jian Ding,Na Wei,Ying Cai,Xin-Ran Liu,Xin Cao,Yi Chen,Zhi-Jiang Wu,Miao Ding,and Ming Zuo 617
21.1 Cancer Targeting Gene-Viro-Therapy with Excellent Antitumor Effects 618
21.1.1 The CTGVT with Potent Antitumor Effect 618
21.1.2 Modification of CTGVT by the Use of Two Genes,CTGVT-DG 618
21.1.3 Other Modification of CTGVT 621
21.2 Super Interferon(sIFN-I)with Super Antitumor Effects on Solid Tumor in Animals and in Patients 622
21.2.1 sINF-I with Super Antitumor Effect on Solid Tumor in Animal Models 624
21.2.2 sIFN-I with Super Antitumor Effects on Solid Tumor in Patients 630
21.2.3 Mechanism of sIFN-I Action 641
21.2.4 Discussion concerning the action of IFN or sIFN-I Briefly 643
21.2.5 Summary of sIFN-I 647
21.3 Cytokine-Induced Killer Cell Therapy and its Important Modification 647
21.3.1 Background 647
21.3.2 Characteristics of CIK Cells 648
21.3.3 Clinical Studies of CIK 648
21.3.4 Modification and Future Prospective of CIK 651
21.3.5 Summary of CIK Therapy 652
21.4 Antibody Protein Therapy and Antibody Gene Therapy or Armed Antibody Gene Therapy 652
21.4.1 Antitumor Protein(mAb)Therapy 652
21.4.2 Immune Therapy Steps Up the Attack 653
21.4.3 Antibody Gene Therapy and Armed Antibody Gene Therapy 653
21.5 Cancer Crusade at 40 654
21.5.1 Introduction:Celebrating an Anniversary(by Paula Kiberstis and Eliot Marshall) 654
21.5.2 Cancer Research and the 90 Billion USD Metaphor(by Eliot Marshall) 655
21.5.3 Combining Target Drug to Stop Resistant Tumors(by Jocelyn Kaiser) 656
21.5.4 Exploring the Genomes of Cancer Cells:Progress and Promise(by M.R.Stratton) 657
21.5.5 A Perspective on Cancer Cell Metastasis(by Christine Chaffer and Robert A.Weinberg) 658
21.5.6 Cancer Immunoediting:Integrating Immunity's Roles in Cancer Suppression and Promotion(by R.D.Schreiber,L.J.Old,and M.J.Smyth) 661
21.6 Conclusion 663
About the Editors 673