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Sensitization of Cancer Cells for Chemo/Immuno/Radio-therapy
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Sensitization of Cancer Cells for Chemo/Immuno/Radio-therapy
von: Benjamin Bonavida
Humana Press, 2008
ISBN: 9781597454742
420 Seiten, Download: 6785 KB
 
Format:  PDF
geeignet für: Apple iPad, Android Tablet PC's Online-Lesen PC, MAC, Laptop

Typ: B (paralleler Zugriff)

 

 
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Inhaltsverzeichnis

  Preface 6  
  Table of Contents 10  
  Contributors 14  
  Color Plates 20  
  Part I: Sensitization via Membrane-Bound Receptors 24  
     Chapter 1 25  
        Sensitization of Epithelial Cancer Cells with Human Monoclonal Antibodies 25  
           1 Natural IgM Antibodies 25  
           2 Growth Factor Receptors 25  
           3 Complement Decay Molecules 26  
           4 Heat Shock Proteins 28  
           5 Summary 30  
           References 30  
     Chapter 2 35  
        Targeting the Transferrin Receptor to Overcome Resistance to Anti-Cancer Agents 35  
           1 The Transferrin Receptor 35  
           2 Tf Conjugates to Overcome Chemoresistance 36  
           3 TfR Targeted Liposomal Delivery of Chemotherapeutic Drugs 41  
           4 TfR Targeted Liposomal Gene Therapy to Sensitize Cells to Chemotherapy 41  
              4.1 Human alpha Folate Receptor Oligodeoxyribonucleotide Delivery 42  
              4.2 Bcl-2 Oligodeoxyribonucleotide Delivery 42  
              4.3 Wild-Type p53 Gene Delivery 42  
           5 Anti-TfR antibodies and Their Conjugates For Sensitization of Tumors to Chemotherapy 43  
           6 A Universal Delivery System for Targeted Cancer Therapy 44  
           7 Conclusion 47  
           References 47  
     Chapter 3 51  
        Chemo-Immunosensitization of Resistant B-NHL as a Result of Rituximab (anti-CD20 mAb)-Mediated Inhibition of Cell Survival Signaling Pathways 51  
           1 Introduction 51  
           2 Rituximab-Mediated Inhibition of Constitutively Activated Cell Survival Anti-Apoptotic Signaling Pathways: Pivotal Role in Chemosensitization of Drug-Resistant B-NHL 52  
              2.1 Rituximab-Mediated Inhibition of Tumor-Derived Resistance Factor(s): Role of the p38 MAPK Signaling Pathway in Resistance 52  
              2.2 Rituximab-Mediated Inhibition of the Raf-1/MEK1/2/ERK1/2/AP-1 Pathway: Pivotal Role in Inhibition of Bcl-2/Bcl-xL and Chemosensitization 53  
              2.3 Rituximab-Mediated Inhibition of the NF-kB Signaling Pathway: Pivotal Role in the Inhibition of Bcl-xL Transcription, Expression, and Chemosensitization 53  
              2.4 Rituximab-Mediated Inhibition of the Akt/PI3K Pathway: Pivotal Role in the Inhibition of Phospho-Bad and Augmentation of Associations of Bad with Bcl-xL 54  
           3 Rituximab-Mediated Inhibition of Constitutively Activated and Overexpressed NF-kB and YY1 Repressor Activities: Pivotal Role in Sensitization to Cytotoxic Ligands (Fas-L, TRAIL) via Upregulation of Corresponding Death Receptors 54  
              3.1 Rituximab Sensitizes B-NHL Cell Lines to Fas-L-Induced Apoptosis: Pivotal Role of YY1 Inhibition and Up-regulation of Fas Expression 54  
              3.2 Rituximab Sensitizes B-NHL Cells to TRAIL-Induced Apoptosis: Pivotal Role of YY1 Inhibition and Upregulation of DR5 Expression 55  
           4 Development of Resistance to Rituximab Treatment: Reversal of Resistance by Pharmacologic Inhibitors Targeting the Constitutively Hyperactivated/ Survival Anti-apoptotic Signaling Pathways 56  
           5 Concluding Remarks 57  
           6 Summary 59  
           References 59  
     Chapter 4 63  
        Agents that Regulate DR5 and Sensitivity to TRAIL 63  
           1 TRAIL-DR5 Pathway 63  
              1.1 Agents That Regulate DR5 and Sensitivity to TRAIL 63  
                 1.1.1 Conventional Anti-tumor Agents 65  
                 1.1.2 New-Age Anti-tumor Agents 65  
                 1.1.3 Food Components 66  
                 1.1.4 Other Agents 67  
              1.2 Other Systems Sensitizing TRAIL 67  
              1.3 Future Direction 67  
              References 68  
     Chapter 5 73  
        Proteasome Inhibition: Potential for Sensitization of Immune Effector Mechanisms in Cancer 73  
           1 Introduction 73  
           2 Proteasome Inhibition in Immune-Mediated Disorders 74  
           3 Use of Proteasome Inhibitors to Create Cellular Sensitization to Death Pathways 76  
           4 Bortezomib and CDDO 78  
           References 79  
  Part II: Sensitization via Inhibition of Cell Survival Pathways (Excluding Apoptotic Signaling Pathways) 83  
     Chapter 6 85  
        Angiogenesis Inhibitors as Enabling Agents for the Chemotherapeutic Treatment of Metastatic Disease 85  
           1 Introduction 85  
           2 Historical Perspective 86  
           3 Preclinical Studies 87  
              3.1 Bevacizumab Therapy Experiments in Preclinical Tumor Models, Including Metastatic Models 87  
              3.2 Metronomic (Antiangiogenic) Chemotherapy in Preclinical Models and Metastasis Therapy Experiments 89  
              3.3 Proposed Mechanisms of Action for Bevacizumab and Metronomic Chemotherapy 90  
                 3.3.1 Metronomic Chemotherapy 90  
                 3.3.2 Bevacizumab 91  
              3.4 Proposed Mechanisms to Explain the Effectiveness of Angiogenesis Inhibitors as Chemosensitizing Agents 91  
                 3.4.1 Induction of “Vessel Normalization” 91  
                 3.4.2 Blunting Tumor Repopulation 91  
                 3.4.3 Augmentation of the Antivascular Effects of Chemotherapy by Targeting Circulating Bone Marrow-Derived Endothelial Progenitor Cells 92  
                 3.4.4 Targeting the Vascular Cancer Stem Cell Niche in Order to Enhance the Activity of Cytotoxic Therapy Toward Cancer Stem Cells 92  
              3.5 Toxicity Associated with Combinations of Angiogenesis Inhibitors and Chemotherapy 92  
              3.6 Complex Therapeutic Combination Regimens 93  
           4 Clinical Aspects 93  
              4.1 Single-Agent Antiangiogenic Therapy 93  
              4.2 Combination Therapies 95  
                 4.2.1 Bevacizumab Combined with Conventional Chemotherapy 95  
                 4.2.2 Targeted Antiangiogenic Drugs Combined with Low-Dose Metronomic Chemotherapy 96  
                 4.2.3 Antiangiogenic RTKIs Combined with Conventional Chemotherapy 96  
              4.3 Future Challenges 97  
                 4.3.1 Dosing 97  
                 4.3.2 Timing 97  
                 4.3.3 Tumor Stage 97  
                 4.3.4 Type of Cytotoxic Drug(s) Used in Combination Regimens 97  
           5 Turning The Current Dogma Upside Down 97  
           6 Conclusion 98  
           References 99  
     Chapter 7 103  
        Targeting Survival Cascades Induced by Activation of Ras/Raf/MEK/ERK and PI3K/Akt Pathways to Sensitize Cancer Cells to Therapy 103  
           1 Overview of the Ras/Raf/MEK/ERK Pathway 103  
           2 Overview of the PI3K/Akt Pathway 104  
           3 Interactions Between PI3K/Akt and Raf/MEK/ERK Pathways That Regulate Apoptosis 105  
           4 Roles of the Ras/Raf/MEK/ERK Pathway in Neoplasia 108  
           5 Roles of the PI3K/Akt Pathway in Neoplasia 110  
           6 Signaling Pathways and Hematopoietic Cancer 110  
           7 Targeted Therapy in AML 111  
           8 Signaling Pathways and Breast Cancer 112  
           9 Aberrant Regulation of Apoptosis May Contribute to Breast Cancer and Subsequent Drug Resistance 113  
           10 Signaling Pathways and in Prostate Cancer 114  
           11 Therapeutic Targeting of the Raf/MEK/ERK, PI3K/Akt, and Apoptotic Pathways 115  
           12 Combination Therapies to Enhance Toxicity 117  
           13 Combining Signal Transduction Inhibitors with Antibody-, Hormonal-, and Chemotherapeutic-Based Therapies 118  
           14 Enhancing the Effects of Ras/Raf/MEK/ERK Pathway Inhibitors by Combination Therapy 119  
           15 Role of the Raf/MEK/ERK Pathway in Drug Resistance to Reactive Oxygen Intermediate-Inducing Cancer Treatments 120  
           16 Conclusions 121  
           References 123  
     Chapter 8 137  
        Histone Deacetylase Inhibitors and Anticancer Activity 137  
           1 Introduction 137  
           2 Histone Deacetylases: HDAC Inhibitors 137  
           3 HDAC Inhibitors in Cancer Therapy: Molecular Mechanisms 139  
              3.1 HDACIs and Epigenetics 139  
              3.2 HDAC Inhibitors and Generation of Reactive Oxygen Species 140  
              3.3 Effects of HDACIs on the Extrinsic, Receptor-Mediated Apoptotic Pathway 141  
              3.4 HDAC Inhibitors and NF-.B Activity 142  
              3.5 Generation of the Pro-apoptotic Lipid Second Messenger Ceramide 143  
              3.6 HDACIs and Modulation of Heat Shock Proteins 143  
              3.7 HDACI-Mediated Effects on the DNA Repair Pathway 144  
              3.8 HDACIs and Disruption of the G2M Checkpoint 145  
              3.9 HDACIs and E2F1-Mediated Induction of Bim 145  
           4 Summary and Conclusions 145  
           References 146  
     Chapter 9 155  
        Eicosanoids and Resistance of Cancer Cells to Chemotherapeutic Agents 155  
           1 Introduction 155  
           2 Cellular Synthesis of Eicosanoids 155  
              2.1 Prostanoids 155  
              2.2 Leukotrienes 157  
              2.3 EETs and HETEs 158  
           3 Signaling by Eicosanoids 158  
           4 Biological Function of Eicosanoids 160  
              4.1 Inflammation 160  
              4.2 Immunity 160  
              4.3 Apoptosis 161  
           5 Arachidonic Acid Pathways in Oncogenesis 161  
              5.1 Involvement of Eicosanoids in Common Cancer Types 161  
              5.2 Trials for the Prevention of Colorectal Adenomas and Cox-2 Inhibitors 162  
           6 Mechanisms of Eicosanoid-Mediated Resistance to Chemotherapeutic Agents 163  
              6.1 Resistance to Apoptosis Is One of the Reasons for the Failure of Chemotherapy 163  
              6.2 Contribution of Eicosanoid-Independent Effects of Cox-2 164  
              6.3 Eicosanoids Promote Tumor Growth via Modulation of Non-Cancer Cells 164  
              6.4 Eicosanoids Promote Proliferation and Invasiveness of Cancer Cells 165  
              6.5 Cross-activation of Receptor Signaling Pathway Downstream Components 165  
              6.6 Expression of ABC Transporters 166  
              6.7 Stimulation of Pro-survival Signaling Pathways 167  
           7 Concluding Remarks 169  
           References 170  
  Part III: Sensitization via Transcription Factors 179  
     Chapter 10 181  
        The RKIP and STAT3 Axis in Cancer Chemotherapy: Opposites Attract 181  
           1 Chemotherapy and the Regulation Apoptosis in Cancer 181  
              1.1 The Role of NF-.B 181  
           2 The Role of the JAK/STAT Pathway 182  
              2.1 STAT Activation and Inactivation Require Multiple Post-Translational Modifications 182  
              2.2 STAT Proteins Need Post-translational Modifications on Lysine Residues 183  
              2.3 STAT3 Is an Oncogene and Plays a Role In Both Cell Growth and Metastasis 184  
              2.4 Targeting STAT3 for Chemotherapy 185  
           3 RKIP, an Inhibitor of Cell Survival Pathways and Inducer of Chemotherapy-Triggered Apoptosis 185  
              3.1 RKIP: An Inhibitor of Raf and NF-.B Cell Survival Signaling 185  
              3.2 RKIP Knockout Mouse Develops Olfaction Deficits 186  
              3.3 RKIP Inhibits Tumor Progression 187  
              3.4 RKIP Is a Metastasis Suppressor 187  
              3.5 RKIP: A Regulator of Chemotherapy-Triggered Apoptosis 187  
           4 RKIP and STAT3: Where’s the Connection? 188  
           5 RKIP Inhibits IL-6-Mediated Cell Proliferation 188  
              5.1 RKIP Inhibits IL-6-Mediated STAT3 Activation 188  
              5.2 RKIP Inhibits JAK 1, 2-Mediated STAT3 Activation 189  
              5.3 Inverse Association Between RKIP and STAT3 with Clinical Outcome in Gastric Cancer Patients 189  
           6 Concluding Remarks 191  
           References 191  
     Chapter 11 197  
        Targeting Transcription Factors with Decoy Oligonucleotides: Modulation of the Expression of Genes Involved in Chemotherapy Resistance of Tumor Cells 197  
           1 Introduction 197  
           2 Apoptosis and Chemotherapy Resistance of Tumor Cells 197  
           3 Nuclear Factor kappa-B and Tumor Chemoresistance 198  
           4 Estrogen Receptors and Chemoresistance in Breast Cancer Cells 198  
           5 Oligonucleotides and Chemoresistance of Tumor Cells 199  
              5.1 Antisense Oligonucleotides 200  
              5.2 The RNA Interference Strategy 200  
           6 The Transcription Factor Decoy Approach for Alteration of Gene Expression 201  
           7 Inhibition of NF-kB Activity by TFD Molecules 201  
           8 Induction of ERalpha Gene Expression by TFD Molecules 203  
           9 Conclusions and Perspectives 203  
           References 205  
     Chapter 12 211  
        p53 Inhibitors as Cancer Sensitizing Agents 211  
           1 The p53 Player: A Stage Director for the Fate of Stressed Cells 211  
           2 Dominant or Discrete Action of p53 Depending on the Cellular Context 213  
              2.1 Lessons from Mouse Development 213  
              2.2 Human Diseases and p53: An Unavoidable Match 213  
              2.3 Side Effects of Cancer Therapy: Once Again p53 is Dictating the Rules 214  
              2.4 But p53 is Not Only a Killer 215  
           3 Is p53 Inhibition a Desirable Target for Human Cancer Therapy? 215  
              3.1 Inhibition of p53 to Reduce Side Effects of Radiotherapy and Chemotherapy 216  
              3.2 Inhibition of p53 as Apoptosis-Sensitizing Strategy 216  
           4 Chemistry and Biology Together for a Common Goal: Shoot p53 217  
              4.1 Pifithrin-alpha Opened the Way 217  
              4.2 Derivatives of Pifithrin-alpha Can Do Even Better 218  
              4.3 Proper Formulation of p53 Inhibitors Can Optimize Delivery and Efficacy, Reducing Risks 219  
           5 Conclusion 220  
           References 220  
     Chapter 13 225  
        Nitric Oxide-Induced Immunosensitization to Apoptosis by Fas-L and TRAIL 225  
           1 Introduction 225  
           2 Biological Activity of Nitric Oxide 226  
           3 Sensitization of Tumor Cells to Fas-L-Induced Apoptosis by IFN-gamma: Pivotal Role of NO 226  
           4 Sensitization of Tumor Cells to TRAIL-Induced Apoptosis by NO: Roles of NF-kB and Bcl-xL 228  
           5 Sensitization of Tumor Cells to TRAIL-Induced Apoptosis by NO: Roles of YY1 and DR5 228  
           6 Concluding Remarks 230  
           References 231  
     Chapter 14 233  
        Natural Agents That Can Sensitize Tumor Cells to Chemotherapy and Radiation Therapy 233  
           1 Introduction 233  
           2 Molecular Mechanisms of Chemoresistance and Radioresistance 234  
              2.1 Nuclear Factor-.B 234  
              2.2 Activator Protein-1 237  
              2.3 Cyclooxygenase 237  
              2.4 Bcl-2 238  
              2.5 Survivin 238  
              2.6 Epidermal Growth Factor Receptor 238  
              2.7 Akt 238  
              2.8 Signal Transducer and Activator of Transcription 3 238  
              2.9 Multidrug Resistance Protein 239  
           3 Chemosensitizing Polyphenols 239  
              3.1 Curcumin 239  
              3.2 Resveratrol 240  
              3.3 Genistein 241  
              3.4 Epigallocatechin Gallate 242  
              3.5 Silymarin 243  
              3.6 Quercetin 244  
              3.7 Emodin 244  
              3.8 Flavopiridol 245  
           4 Radiosensitizing Polyphenols 246  
              4.1 Curcumin 246  
              4.2 Resveratrol 247  
              4.3 Genistein 247  
              4.4 EGCG 248  
              4.5 Flavopiridol 248  
           5 Conclusions 249  
           References 250  
  Part IV: Sensitization via Targeting Apoptotic Pathways 263  
     Chapter 15 265  
        Inhibitors of the Bcl-2 Protein Family as Sensitizers to Anticancer Agents 265  
           1 Introduction 265  
           2 Pathways of Apoptosis 265  
           3 The Bcl-2 Protein Family 267  
           4 Antisense Strategies to Inhibit Expression of Bcl-2 Family Members 268  
           5 Structural Studies of Bcl-2 Family Members 269  
           6 BH3 Peptides 270  
           7 Nonpeptidic, Small Molecule Inhibitors of Bcl-2 Family Members 271  
              7.1 ABT-737 271  
              7.2 Gossypol, Apogossypol, and TW-37 272  
              7.3 Antimycin A3 273  
              7.4 HA14-1 274  
              7.5 BH3Is 274  
              7.6 Tea Polyphenols 274  
              7.7 Chelerythrine and Sanguinarine 275  
              7.8 Other Inhibitors 275  
           8 Conclusions 275  
           References 276  
     Chapter 16 285  
        Chapter 16Therapeutic Targeting of Apoptosis in Cancer 285  
           1 Introduction 285  
              1.1 Apoptosis 285  
              1.2 Intrinsic Pathway 287  
              1.3 Extrinsic Pathway 287  
              1.4 Inhibitors of Apoptosis Proteins 288  
              1.5 Survival Pathways 289  
           2 Correlation of Apoptotic Proteins with Disease Response 289  
              2.1 Death Receptor Pathway 289  
              2.2 Bcl-2 Family 290  
              2.3 Inhibitors of Apoptosis Proteins 290  
           3 Targeting Apoptosis 291  
              3.1 Extrinsic Pathway 291  
              3.2 Intrinsic Pathway 292  
              3.3 IAPs 293  
              3.4 Survival Pathways 293  
           4 Conclusions and Future Perspectives 294  
           References 294  
     Chapter 17 301  
        Peptides and Peptidomimetics as Cancer Therapy Sensitizing Agents 301  
           1 Introduction 301  
           2 Antiangiogenic Peptides and Peptidomimetics as Cancer Sensitizing Agents 301  
           3 Peptides Targeting Bcl-2 and Bcl-xL Proteins 305  
           4 Peptide-Based Targeting of Protein Kinases in Cancer Therapy 306  
           5 Inducing Tumor Apoptosis Using Smac Peptidomimetics 309  
           6 Clinical Utility of Peptides 312  
           7 Roles for Peptide-Based Targeting in Cancer Therapy 313  
              7.1 Tumor-Specific Targeting 313  
              7.2 Drug Delivery 313  
           8 Experience with Peptide-Targeted Therapy 313  
           9 Limitations to the Use of Peptide Targeted Therapy 314  
           10 The Use of Peptides in Vaccination Against Cancer 314  
           11 Epilogue 319  
           References 320  
     Chapter 18 327  
        Non-Peptidic Mimetics as Cancer-Sensitizing Agents 327  
           1 Introduction 327  
           2 Designing a Non-Peptidic Mimetic 327  
              2.1 Structure Analysis 328  
              2.2 Structure-Activity Relationships 328  
              2.3 The Pharmacophore Site 328  
              2.4 Non-Peptidic Mimetic Design Strategies 328  
           3 Non-Peptidic Mimetics in Action 329  
              3.1 p53-HDM2 Mimetic 329  
                 3.1.1 Cyclized Peptide Mimetic 329  
                 3.1.2 Terphenyl Scaffolded Mimetic 330  
              3.2 CDK2 Mimetic 330  
              3.3 Mimetics of Proteins Involved in Apoptosis 330  
                 3.3.1 Pro-apoptotic Protein BID 331  
                 3.3.2 Mimetics of the BH3 Domain of Bak 331  
                 3.3.3 BH3 Mimetics 332  
                 3.3.4 Smac Mimetics 332  
              3.4 Tumor Suppressor Mimetic 332  
              3.5 Mimetics of Translational Initiation Factors 332  
              3.6 Mimetic of the Syk C-Terminal SH2 Domain 333  
              3.7 Mimetics of Proteins Involved in Angiogenesis 333  
                 3.7.1 Mimetics of Growth Factors 333  
                    3.7.1.1 Growth Factor Mimetics 333  
                    3.7.1.2 Tyrosine Kinase Inhibitors 334  
                 3.7.2 TNP-470 335  
                 3.7.3 Thalidomide 335  
                 3.7.4 Squalamine 335  
                 3.7.5 Galectin-1 Antagonist 335  
                 3.7.6 RGD Mimetic 336  
                 3.7.7 Others 336  
                    3.7.7.1 Almost There 337  
                    3.7.7.2 Thrombospondin-1 337  
                    3.7.7.3 Prolactin/Growth Hormone Family Members 337  
                    3.7.7.4 Endostatin 338  
                 3.7.8 MMP Inhibitors 338  
           4 Combination Therapy 338  
              4.1 Radiation Therapy 339  
              4.2 Chemotherapy 340  
           5 Future Directions 341  
           References 341  
     Chapter 19 349  
        Sensitization of Cancer Cells to Cancer Therapies by Isoflavone and Its Synthetic Derivatives 349  
           1 Introduction 349  
           2 Antitumor Activity of Conventional Cancer Therapies Are Enhanced by Isoflavone and Its Derivatives 350  
              2.1 Potentiation of Chemotherapeutic Effects by Isoflavone and Its Derivatives 350  
                 2.1.1 Isoflavone Genistein 350  
                 2.1.2 Isoflavone Derivatives 351  
                    2.1.2.1 Phenoxodiol 351  
                    2.1.2.2 FPA-120 to FPA-127 352  
                    2.1.2.3 Other Isoflavone Derivatives 353  
              2.2 Potentiation of Radiotherapy Effects by Isoflavone 353  
           3 Molecular Mechanisms of Cancer Cell Sensitization to Conventional Cancer Therapy by Isoflavone and Its Derivatives 354  
              3.1 Regulation of the Akt Pathway 354  
              3.2 Regulation of NF-.B Pathway 354  
              3.3 Regulation of Apoptosis Pathways 354  
              3.4 Regulation of Other Pathways 355  
           4 Conclusion and Perspective 355  
           References 355  
     Chapter 20 359  
        Antisense Oligonucleotides and siRNA as Specific Inhibitors of Gene Expression: Mechanisms of Action and Therapeutic Potential 359  
           1 Introduction 359  
           2 Mechanisms of Action 359  
              2.1 Antisense Oligonucleotides 359  
              2.2 siRNA 360  
           3 Chemical Modification and Pharmacologic Properties 360  
              3.1 Antisense Oligonucleotides 360  
                 3.1.1 First-Generation AS-ODNs 361  
                 3.1.2 Second-Generation AS-ODNs 362  
                 3.1.3 Third-Generation AS-ODNs 362  
              3.2 siRNA 362  
           4 AS-ODN and siRNA Selection 364  
           5 Toxicity of AS-ODN and siRNA 366  
           6 Therapeutic Potential of AS-ODNs and siRNAs 366  
              6.1 Brain Cancer 366  
                 6.1.1 Protein Kinase c-Alpha 366  
                 6.1.2 Epidermal Growth Factor Receptor 366  
                 6.1.3 Transforming Growth Factor-beta 367  
              6.2 Prostate Cancer 367  
                 6.2.1 Bcl-2 367  
                 6.2.2 Clusterin 367  
                 6.2.3 Urokinase Plasminogen Activator Receptor 367  
                 6.2.4 PKC-alpha 368  
                 6.2.5 c-raf or raf-1 368  
                 6.2.6 Heat Shock Protein 27 368  
              6.3 Bladder Cancer 368  
                 6.3.1 Clusterin 368  
                 6.3.2 Hsp27 369  
                 6.3.3 Vascular Endothelial Growth Factor 369  
              6.4 Lung Cancer 369  
                 6.4.1 PKC-alpha 369  
                 6.4.2 Bcl-2 369  
              6.5 Breast Cancer 369  
                 6.5.1 Her-2 (c-erbB-2, Neu) 369  
                 6.5.2 Bcl-2 370  
                 6.5.3 Integrins 370  
                 6.5.4 Mouse Double Minute 2 370  
                 6.5.5 CXCR4 370  
                 6.5.6 Type I Insulin-Like Growth Factor 370  
              6.6 Pancreatic Cancer 371  
                 6.6.1 K-ras 371  
                 6.6.2 Hypoxia-Inducible Factor 1alpha 371  
                 6.6.3 Survivin 371  
                 6.6.4 H-ras 371  
                 6.6.5 VEGF 372  
           7 AS-ODNs and siRNAs in Treatment of Nonmalignant Diseases 372  
              7.1 Amyotrophic Lateral Sclerosis 372  
              7.2 Alzheimer’s Disease 372  
              7.3 Human Immunodeficiency Virus Type I 372  
              7.4 Respiratory Diseases 372  
              7.5 Crohn’s Disease 373  
              7.6 Hepatitis C Virus 373  
           References 373  
  Part V: Sensitization Tailored to Individual Patients 385  
     Chapter 21 387  
        DNA Polymorphisms Affecting Chemosensitivity Toward Drugs 387  
           1 Introduction 387  
              1.1 Heterogeneity of Drug Response and Pharmacogenetics 387  
              1.2 Gene Polymorphisms 387  
           2 Monogenic Diseases: Glucose-6-Phosphate Dehydrogenase Deficiency 388  
           3 Complex Diseases: Cancer 389  
              3.1 The Resistance Problem 389  
              3.2 Upstream Mechanisms 391  
                 3.2.1 Drug Transporters 391  
                    3.2.1.1 P-Glycoprotein (ABCB1, MDR1) 391  
                    3.2.1.2 Multidrug Resistance-Related Proteins 392  
                    3.2.1.3 Breast Cancer-Related Protein 393  
                 3.2.2 Drug-Metabolizing Phase I Enzymes 393  
                    3.2.2.1 Cytochrome P450 Monooxygenases 393  
                 3.2.3 Drug-Metabolizing Phase II Enzymes 393  
                    3.2.3.1 UDP-Glucuronosyltransferases 394  
              3.3 Drug Target Interactions 394  
                 3.3.1 DNA Biosynthesis and Metabolism 394  
                    3.3.1.1 Thiopurine S-Methyltransferase 394  
                    3.3.1.2 Thymidylate Synthase 395  
                    3.3.1.3 5,10-Methylenetetrahydrofolate Reductase 395  
              3.4 DNA Repair Mechanisms 395  
                 3.4.1 HO6-Methylguanine-DNA Methyltransferase 395  
                    3.4.1.1 X-Ray Cross-Complementation Group 1 Gene 396  
                    3.4.1.2 Excision-Repair Cross-Complementing Genes 1 and 2 397  
              3.5 Downstream Mechanisms 397  
                 3.5.1 Tumor Suppressor p53 397  
                 3.5.2 BAX 398  
           4 Synopsis and Perspectives 398  
           References 399  
     Chapter 22 411  
        Pharmacogenetics in Cancer Management: Scenario for Tailored Therapy 411  
           1 Introduction 411  
           2 Drug Metabolism 411  
              2.1 Phase I Metabolism 412  
                 2.1.1 Cytochrome p450 Isoform 2C8 412  
                 2.1.2 Cytochrome p450 Subfamily 3A 412  
                 2.1. 3 CYP3A4 412  
                 2.1.4 Cytochrome p450 Isoform 2B6 413  
              2.2 Phase II Metabolism 413  
                 2.2.1 Uridine Diphosphate Glucuronosyltransferase 413  
                 2.2.2 Glutathione S-Transferases 414  
           3 Drug Transport 415  
              3.1 Multidrug Resistance Gene 1 and Multidrug Resistance Associated Protein 2 415  
           4 Mechanism of Action of Drugs 416  
              4.1 Folate Pathway 416  
                 4.1.1 Thymidylate Synthase and Dihydropyrimidine Dehydrogenase 416  
                 4.1.2 Methylene Tetrahydrofolate Reductase 417  
              4.2 DNA Repair Pathway 417  
                 4.2.1 X-Ray Repair Cross-Complementing Isoform 1 417  
                 4.2.2 Xeroderma Pigmentosum Group D 418  
                 4.2.3 Excision Repair Cross Complementing Group 1 419  
           5 Conclusion 420  
           References 420  
  Index 427  
  Color Plates 442  


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