Dai Checkpoint Responses in Cancer Therapy

1. Auflage 2008
ISBN: 978-1-59745-274-8
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 314 Seiten

Reihe: Cancer Drug Discovery and Development

Extensive research has uncovered a set of molecular surveillance mechanisms - commonly called 'checkpoints' - which tightly monitor cell-cycle processes. Today's anticancer drug development has identified many of these cell-cycle checkpoint molecules as effective targets. Research now promises to uncover a new generation of anticancer drugs with improved therapeutic indices based on their ability to target emerging checkpoint components. Checkpoint Responses in Cancer Therapy summarizes the advances made over the past 20 years, identifying components of cell-cycle checkpoints and their molecular regulation during checkpoint activation and validating the use of checkpoint proteins as targets for the development of anticancer drugs. This book's distinguished panel of authors takes a close look at topics ranging from the major molecular players affecting DNA synthesis and the response to DNA damage to advances made in the identification of chemical compounds capable of inhibiting individual mitotic kinases. Illuminating and authoritative, Checkpoint Responses in Cancer Therapy offers a critical summary of findings for researchers in the pharmaceutical and biotechnology industries and a valuable resource for academic scientists in cancer research and the study of cell-cycle regulation, signal transduction and apoptosis.

Autoren/Hrsg.

Dai, Wei

Inhaltsverzeichnis

1;Preface;6
2;Contents;10
3;Contributors;12
4;RB-Pathway;15
4.1;CONTENTS;15
4.2;1. DYSREGULATION OF THE RB PATHWAY IN CANCER;16
4.3;2. CELL CYCLE CONTROL THROUGH THE RB- PATHWAY;17
4.3.1;2.1. The RB Pathway in S-Phase Control;18
4.3.2;2.2. Involvement of RB Pathway in G2/M Control;19
4.4;3. INFLUENCE OF THE RB-PATHWAY GENOTOXIC THERAPIES;19
4.5;4. IMPACT OF RB PATHWAY ON ANTIMETABOLITES;20
4.6;5. INFLUENCE OF RB ON ANTIMICROTUBULE AGENTS;21
4.7;6. TARGETED THERAPEUTICS AND THE IMPACT OF RB PATHWAY;21
4.7.1;6.1. Staurosporine and 7-Hydoxystaurosporine;21
4.7.2;6.2. Geldanamycins;22
4.7.3;6.3. CDK Inhibitors;22
4.8;7. SYNOPSIS;23
4.9;ACKNOWLEDGMENTS;23
4.10;REFERENCES;23
5;Targeting the p53/MDM2 Pathway for Cancer Therapy;33
5.1;CONTENTS;33
5.2;1. INTRODUCTION;33
5.3;2. THE p53 TUMOR SUPPRESSOR PROTEIN;34
5.4;3. REACTIVATION OF MUTANT p53 IN TUMORS;37
5.5;4. INHIBITION OF THE p53-MDM2 INTERACTION;42
5.5.1;4.1. Function and Structure of MDM2;42
5.5.2;4.2. Validation of MDM2 as a Target;45
5.5.3;4.3. Peptidic Inhibitors of the p53-MDM2 Interaction;46
5.5.4;4.4. Small-Molecule Inhibitors of the p53-MDM2 Interaction;47
5.6;5. INHIBITION OF MDM2 E3 LIGASE ACTIVITY;53
5.7;6. MODULATION OF p53 ACTIVITY FOR PROTECTION OF NORMAL TISSUES DURING CHEMOTHERAPY;54
5.8;REFERENCES;55
6;DNA Topoisomerases as Targets for the Chemotherapeutic Treatment of Cancer;71
6.1;CONTENTS;71
6.2;1. INTRODUCTION;72
6.3;2. DNA TOPOLOGY AND TOPOISOMERASES;73
6.3.1;2.1. Type I Topoisomerases;74
6.3.2;2.2. Type II Topoisomerases;75
6.4;3. TOPOISOMERASE-TARGETED ANTICANCER DRUGS;77
6.4.1;3.1. Topoisomerase I-Targeted Drugs;77
6.4.2;3.2. Topoisomerase II-Targeted Drugs;80
6.5;4. OTHER TOPOISOMERASE POISONS;82
6.5.1;4.1. Bioflavonoids;82
6.5.2;4.2. Quinones;83
6.5.3;4.3. DNA Damage;83
6.6;5. TOPOISOMERASE II AND LEUKEMIA;84
6.7;6. CHECKPOINT RESPONSES AND REPAIR OF TOPOISOMERASE- MEDIATED DNA DAMAGE;86
6.7.1;6.1. Checkpoint Responses;86
6.7.2;6.2. Processing Topoisomerases from DNA Termini;88
6.7.3;6.3. Repair of Topoisomerase-Generated DNA Strand Breaks;89
6.8;7. SUMMARY;89
6.9;ACKNOWLEDGMENTS;89
6.10;REFERENCES;90
7;Targeting ATM/ATR in the DNA Damage Checkpoint;107
7.1;CONTENTS;107
7.2;1. INTRODUCTION;107
7.3;2. ATM/ATR GENE ORGANIZATION;109
7.4;3. ATM AND ATR ARE KEY MEDIATORS OF THE DNA DAMAGE RESPONSE PATHWAY;109
7.4.1;3.1. Regulation of ATM by Phosphorylation;109
7.4.2;3.2. MRE11/RAD50/NBS1 Complex is a Key Regulator of ATM;111
7.4.3;3.3. ATM is Differentially Activated;113
7.4.4;3.4. ATM Activates Targets at the site of DNA Damage;114
7.4.5;3.5. p53 is a Major ATM Target;115
7.4.6;3.6. ATM Substrates Regulate Cell Cycle Checkpoints;116
7.4.7;3.7. ATR;119
7.5;4. PROSPECTS OF REGULATING ATM/ATR PATHWAYS;121
7.6;REFERENCES;123
8;Compounds that Abrogate the G2 Checkpoint;131
8.1;CONTENTS;131
8.2;1. WHY FOCUS ON THE G2 CHECKPOINT?;132
8.3;2. MOLECULAR MECHANISM OF THE G2 CHECKPOINT;133
8.4;3. SCREENING PROTOCOL TO IDENTIFY G2 CHECKPOINT ABROGATORS;135
8.5;4. CURRENTLY AVAILABLE COMPOUNDS WITH G2 CHECKPOINT- ABROGATING POTENTIAL;136
8.6;5. COMPOUNDS IN THE CLINIC WITH G2 CHECKPOINT- INHIBITING ACTIVITY;138
8.7;6. FUTURE DIRECTIONS;139
8.8;REFERENCES;140
9;CDK Inhibitors as Anticancer Agents;149
9.1;CONTENTS;149
9.2;1. INTRODUCTION;150
9.3;2. CYCLIN-DEPENDENT KINASES;151
9.4;3. THERAPEUTIC CDK INHIBITORS;154
9.4.1;3.1. First Generation CDK Inhibitors;155
9.4.2;3.2. Second Generation CDK Inhibitors;160
9.4.3;3.3. Key Issues with CDK Inhibitors;164
9.5;4. FUTURE STRATEGIES;166
9.6;REFERENCES;167
10;CHFR as a Potential Anticancer Target;177
10.1;CONTENTS;177
10.2;1. INTRODUCTION;178
10.3;2. IDENTIFICATION OF CHFR;179
10.4;3. THE ROLE OF CHFR IN THE EARLY PROPHASE CHECKPOINT;179
10.5;4. MOLECULAR MECHANISMS MODIFYING CHFR FUNCTION;182
10.6;5. GENETIC AND EPIGENETIC ALTERATION OF CHFR IN HUMAN TUMORS;182
10.7;6. METHYLATION OF CHFR AS A MOLECULAR MARKER TO PREDICT SENSITIVITY TO MICROTUBULE INHIBITORS;184
10.8;7. CHFR AS A MOLECULAR TARGET FOR CANCER THERAPY;184
10.9;8. CONCLUDING REMARKS;185
10.10;ACKNOWLEDGMENTS;186
10.11;REFERENCES;186
11;Antimicrotubule Agents;191
11.1;CONTENTS;191
11.2;1. TUBULIN, CELLULAR ORGANIZATION AND PROPERTIES;192
11.3;2. TUBULIN INTERACTIVE ANTITUMOR AGENTS: DISCOVERY AND MECHANISM OF ACTION;193
11.3.1;2.1. Discovery;193
11.3.2;2.2. Mechanism of Action;196
11.4;3. CLINICAL DEVELOPMENT AND APPROVED INDICATIONS;197
11.4.1;3.1. Naturally Derived Vinca Alkaloids;197
11.4.2;3.2. Vindesine and Vinorelbine;198
11.4.3;3.3. Paclitaxel;202
11.4.4;3.4. Docetaxel;203
11.5;4. TUMOR RESISTANCE TO TUBULIN INTERACTIVE AGENTS;204
11.6;5. NOVEL TUBULIN INTERACTIVE AGENTS IN CLINICAL DEVELOPMENT;207
11.7;REFERENCES;211
12;Kinesin Motor Inhibitors as Effective Anticancer Drugs;221
12.1;CONTENTS;221
12.2;1. INTRODUCTION;222
12.3;2. KINESINS;222
12.4;3. KSP INHIBITORS;226
12.4.1;3.1. Monastrol;226
12.4.2;3.2. Monastrol Analogues;228
12.4.3;3.3. Quinazolinones;229
12.4.4;3.4. Indole Derivatives;230
12.4.5;3.5. S-;231
12.4.6;Trityl-;231
12.4.7;Cysteine;231
12.4.8;3.6. Dihydropyrrole Derivatives;231
12.4.9;3.7. Other Inhibitors;232
12.5;4. CHEMICALLY MODIFIED ANTISENSE OLIGONUCLEOTIDES;233
12.6;5. CONCLUSION;233
12.7;REFERENCES;234
13;Targeting the Spindle Checkpoint in Cancer Chemotherapy;241
13.1;CONTENTS;241
13.2;1. INTRODUCTION;242
13.3;2. MOLECULAR MECHANISMS OF CHROMOSOME SEGREGATION AND THE SPINDLE CHECKPOINT;243
13.4;3. A DEFECTIVE SPINDLE CHECKPOINT CONTRIBUTES TO TUMORIGENESIS;245
13.5;4. ROLE OF THE SPINDLE CHECKPOINT IN APOPTOSIS CAUSED BY ANTIMITOTIC DRUGS;247
13.6;5. TARGETING THE SPINDLE CHECKPOINT PROTEINS FOR CANCER CHEMOTHERAPY;250
13.7;REFERENCES;251
14;Antiproliferation Inhibitors Targeting Aurora Kinases;257
14.1;CONTENTS;257
14.2;1. INTRODUCTION;258
14.3;2. BIOLOGY OF AURORA KINASES;260
14.3.1;2.1. Aurora A: Regulator of Centrosome & Spindle Assembly;260
14.3.2;2.2. Aurora B: Chromosomal Passenger and Cytokinesis Regulator;262
14.3.3;2.3. Aurora C: Complements Aurora B Functions;263
14.4;3. LINKING AURORA KINASES TO ONCOGENESIS;263
14.5;4. INHIBITORS IN PRE-CLINICAL AND CLINICAL DEVELOPMENT;264
14.5.1;4.1. Dual-Action Aurora Kinase Inhibitors;265
14.5.2;4.2. AstraZeneca (ZM447439 and AZD1152);270
14.5.3;4.3. Vertex-Merck (VX-680);270
14.5.4;4.4. Pfizer-Nerviano Medical Sciences (PHA-680632);271
14.5.5;4.5. Johnson & Johnson (JNJ-7706621);272
14.5.6;4.6. Other Bio-Pharmaceuticals Developing Aurora Kinase Inhibitors;272
14.5.7;4.7. Aurora Inhibitors in Phase I Clinical Trials;273
14.6;5. STRUCTURAL BIOLOGY: INSIGHT INTO AURORA INHIBITION;273
14.6.1;5.1. Aurora A;275
14.6.2;5.2. Aurora B;276
14.7;6. CONCLUSIONS AND FUTURE DIRECTIONS;277
14.8;REFERENCES;278
15;Plks as Novel Targets for Cancer Drug Design;285
15.1;CONTENTS;285
15.2;1. INTRODUCTION;286
15.3;2. STRUCTURAL FEATURES OF PLKS;287
15.3.1;2.1. The Kinase Domain;287
15.3.2;2.2. The Polo-Box Domain;288
15.3.3;2.3. Other Structural Features;288
15.4;3. FUNCTION OF PLKS;288
15.4.1;3.1. DNA Damage Responses;289
15.4.2;3.2. Mitotic Regulation;290
15.5;4. DEREGULATION OF PLKS IN CANCER;290
15.6;5. COMPOUNDS INHIBITING PLKS;291
15.6.1;5.1. Scytonemin;291
15.6.2;5.2. HMN-214;293
15.6.3;5.3. Wortmannin and LY294002;294
15.6.4;5.4. ON01910;295
15.6.5;5.5. BI 2536;295
15.6.6;5.6. Cyclapolin 1;296
15.7;6. ALTERNATIVE APPROACHES TO INHIBIT PLK1;297
15.8;7. SUMMARY;298
15.9;ACKNOWLEDGMENTS;299
15.10;REFERENCES;299
16;Do Histone Deacetylase Inhibitors Target Cell Cycle Checkpoints that Monitor Heterochromatin Structure?;305
16.1;CONTENTS;305
16.2;1. INTRODUCTION;306
16.3;2. CELL CYCLE RESPONSES TO HDACI TREATMENT;307
16.3.1;2.1. HDACi-Induced G1 Phase Arrest;307
16.3.2;2.2. Up-Regulated Expression of p21WAF1/ HDACi Induced Cytotoxicity;311
16.3.3;2.3. HDACi-Induced G2 Phase Checkpoint;311
16.3.4;2.4. HDACi Treatment Disrupts Mitosis and the Spindle Assembly Checkpoint;313
16.4;3. HDACI KILL TUMOR CELLS BY SYNTHETIC LETHALITY;314
16.5;4. MOLECULAR MECHANISM OF HDACI-INDUCED ABERRANT MITOSIS;315
16.6;5. WHY IS THERE AN HDACI SENSITIVE G2 CHECKPOINT?;316
16.7;ACKNOWLEDGMENTS;317
16.8;REFERENCES;317
17;Index;325