Deoxynucleoside Analogs in Cancer Therapy (eBook)

Godefridus J Peters (Herausgeber)

eBook Download: PDF

2007 | 1. Auflage
XIV, 476 Seiten
Humana Press (Verlag)
978-1-59745-148-2 (ISBN)

Infos

Successful cancer chemotherapy relies heavily on the application of various deoxynucleoside analogs. Since the very beginning of modern cancer chemotherapy, a number of antimetabolites have been introduced into the clinic and subsequently applied widely for the treatment of many malignancies, both solid tumors and hematological disorders. In the latter diseases, cytarabine has been the mainstay of treatment of acute myeloid leukemia. Although many novel compounds were synthesized in the 1980s and 1990s, no real improvement was made. However, novel technology is now capable of elucidating the molecular basis of several inborn errors as well as some specific malignancies. This has enabled the synthesis of several deoxynucleoside analogs that could be applied for specific malignancies, such as pentostatin and subsequently chlorodeoxyadenosine (cladribine) for the treatment of hairy cell leukemia. Already in the early stage of deoxynucleoside analog development, it was recognized that several of these compounds were very effective in the treatment of various viral infections, such as for the treatment of herpes infections. This formed the basis initially for the design of azidothymidine and subsequently many other analogs, which are currently successfully used for the treatment of HIV infections. As a spin-off of these research lines, some compounds not eligible for development as antiviral agents appeared to be very potent anticancer agents. The classical example is gemcitabine, now one of the most widely applied deoxynucleoside analogs, used for the (combination) treatment of non-small cell lung cancer, pancreatic cancer, bladder cancer, and ovarian cancer.

Inhalt

PREFACE 6
CONTENTS 10
CONTRIBUTORS 12
Nucleoside Transport Into Cells 15
1. THE CELLULAR REQUIREMENT FOR NUCLEOSIDE SALVAGE IS CRUCIAL TO NUCLEOSIDE- BASED CHEMOTHERAPY 16
2. HOW ARE NUCLEOSIDE-DERIVED DRUGS TRANSPORTED INTO CELLS? 17
2.1. Mechanisms of Nucleoside and Nucleoside-Derived Drug Transport Into Cells 17
2.2. The Nucleoside Transporter Proteins Concentrative Nucleoside Transporter ( SLC28) and Equilibrative Nucleoside Transporter ( SLC29) 18
2.3. The Pharmacological Profiles of CNT and ENT Transporters 24
3. HOW ARE NUCLEOSIDES AND NUCLEOSIDEDERIVED DRUGS RECOGNIZED BY CNT AND ENT PROTEINS? 26
3.1. Structural Determinants for the Molecular Recognition of NT Substrates 27
3.2. Polymorphic NTs 27
4. TISSUE DISTRIBUTION OF NT PROTEINS 28
5. REGULATED VS CONSTITUTIVE NT EXPRESSION: A BASIS FOR DIFFERENTIAL EXPRESSION OF NTs IN TUMORS? 29
6. ROLE OF NTs IN CELL SENSITIVITY TO ANTICANCER DRUGS: FROM DIAGNOSIS TO INDIVIDUALIZED THERAPY? 31
6.1. Analysis of the Role of NTs in Sensitivity to Nucleoside- Derived Anticancer Drugs in Cultured Cell Models 32
6.2. Studies Linking NT Function to Drug Sensitivity and Clinical Outcome in Cancer Patients 34
7. FUTURE PERSPECTIVES 36
ACKNOWLEDGMENTS 36
REFERENCES 37
The Role of Deoxycytidine Kinase in DNA Synthesis and Nucleoside Analog Activation 43
1. INTRODUCTION 45
2. THE EXPRESSION OF dCK IN DIFFERENT CELLS AND TISSUES 49
3. INCREASE OF dCK ACTIVITY BY TREATMENT OF CELLS WITH GENOTOXIC AGENTS: IMPLICATIONS FOR DNA REPAIR AND APOPTOSIS 51
4. PREVENTION OF dCK ACTIVATION BY dCyt AND DEPLETION OF CYTOSOLIC Ca2+ IONS 53
5. DEOXYNUCLEOSIDE ANALOGS ACTIVATED BY dCK 54
6. STRUCTURE–ACTIVITY RELATIONSHIPS OF dCK 56
7. dCK IN CELLS RESISTANT TO TOXIC NUCLEOSIDES 58
8. CONCLUSIONS 60
ACKNOWLEDGMENT 60
REFERENCES 61
Deoxynucleoside Kinases and Their Potential Role in Deoxynucleoside Cytotoxicity 67
1. INTRODUCTION 68
2. THE EVOLUTIONARY ORIGIN OF MULTIPLE dNKs WITH DIFFERENT SUBSTRATE SPECIFICITIES 69
3. PROPERTIES OF HUMAN DEOXYNUCLEOSIDE KINASES 74
3.1. Deoxycytidine Kinase 74
3.2. Cytosolic Thymidine Kinase 75
3.3. Mitochondrial Thymidine Kinase 77
3.4. Mitochondrial Deoxyguanosine Kinase 78
4. NUCLEOSIDE ANALOG SPECIFICITY 79
4.1. Comparison of Substrate Specificities 82
5. SUMMARY AND CONCLUSION 84
REFERENCES 85
Nucleotidases and Nucleoside Analog Cytotoxicity 95
1. INTRODUCTION 96
2. MAINTENANCE OF DEOXYNUCLEOTIDE POOLS 101
2.1. Biosynthetic vs Catabolic Pathways and Substrate Cycles 101
2.2. Separation of Cytosolic, Mitochondrial, and Extracellular Deoxynucleotide Pools 103
3. MAMMALIAN 5'- NUCLEOTIDASES 103
3.1. Ecto- 5'- Nucleotidase 105
3.2. Cytosolic 5'- Nucleotidase IA 106
3.3. Cytosolic 5'- Nucleotidase IB 106
3.4. Cytosolic 5'- Nucleotidase II 107
3.5. Cytosolic 5'- Nucleotidase III 107
3.6. Cytosolic 5'(3')- Deoxyribonucleotidase 108
3.7. Mitochondrial 5'(3')- Deoxyribonucleotidase 109
4. 5'- NUCLEOTIDASES AND DRUG RESISTANCE 109
4.1. cN-II in Nucleoside Analog Metabolism 110
4.2. cN-IA in Nucleoside Analog Resistance 111
4.3. cdN in Nucleoside Analog Resistance 113
4.4. Other Nucleotidases 113
5. 5'- NUCLEOTIDASES: NEW POTENTIAL DRUG TARGETS? 114
REFERENCES 115
Pumping Out Drugs 123
1. INTRODUCTION 124
2. TRANSPORT OF NUCLEOSIDE/NUCLEOTIDE ANALOGS BY MRP4 AND MRP5 126
3. TRANSPORT OF PHYSIOLOGICAL SUBSTRATES BY MRP4 AND MRP5 128
4. TRANSPORT OF NUCLEOTIDE ANALOGS BY MRP8 AND MRP9 128
5. CONCLUDING REMARKS 129
ACKNOWLEDGMENTS 129
REFERENCES 129
Cytosine Arabinoside 133
1. INTRODUCTION 134
2. MECHANISMS OF ACTION AND RESISTANCE 135
2.1. Structure and Metabolism 135
2.2. Transport 136
2.3. Phosphorylation 137
2.4. Drug Degradation 138
3. Ara-C-MEDIATED CYTOTOXICITY 139
3.1. Inhibition of DNA Polymerases and DNA Incorporation 139
3.2. Ara-CTP Accumulation and Retention 139
3.3. S Phase 140
3.4. Intracellular Signaling and Cell Death Pathways 140
4. CLINICAL PHARMACOLOGY OF Ara-C 142
4.1. Pharmacokinetics 142
4.2. Toxicity 142
5. ANTILEUKEMIC ACTIVITY OF Ara-C 143
5.1. Standard Dose Ara-C 145
5.2. High-Dose Ara-C 145
6. Ara-C COMBINATIONS 148
6.1. Modulation of Ara-C-Mediated Cytotoxicity 148
6.2. Ara-C in Combination With Purine Analogs 148
6.3. Ara-C in Combination With Growth Factors 149
6.4. FLAG 150
6.5. Other Approaches to Modulate Ara-C-Induced Cytotoxicity 152
7. Ara-C PRODRUGS 153
8. CONCLUSIONS AND FUTURE PERSPECTIVES 153
REFERENCES 154
Clofarabine 167
1. INTRODUCTION TO THE STRUCTURE 168
2. CATABOLISM 170
3. ANABOLISM 170
4. MECHANISMS OF ACTION 171
5. PRECLINICAL ACTIVITY 173
6. CLINICAL INVESTIGATIONS 173
6.1. Clinical Trials in Adults 174
6.2. Clinical Trials in Pediatric Patients 180
7. SUMMARY 180
ACKNOWLEDGMENT 181
REFERENCES 181
L-Nucleosides as Chemotherapeutic Agents 187
1. INTRODUCTION 189
2. LAMIVUDINE 191
3. EMTRICITABINE 196
4. TELBIVUDINE AND VALTORCITABINE 197
5. CLEVUDINE 198
6. L- 2'- Fd4C 201
7. ELVUCITABINE 202
8. L-I-OddU 205
9. TROXACITABINE 206
ACKNOWLEDGMENT 207
REFERENCES 207
Troxacitabine (Troxatyl™) 213
1. INTRODUCTION 213
2. STRUCTURE AND MECHANISM OF ACTION 214
3. PRECLINICAL EVALUATION 217
4. CLINICAL TRIALS 221
4.1. Solid Tumors 221
4.2. Acute Leukemia 223
5. CONCLUSION 224
ACKNOWLEDGMENT 224
REFERENCES 224
9-ß-D-Arabinofuranosylguanine 229
1. BACKGROUND 230
2. MECHANISM OF ACTION 230
3. CLINICAL USE 232
4. TOXICITY 233
5. RESISTANCE 235
6. CONCLUDING REMARKS 236
REFERENCES 236
Gemcitabine 239
1. INTRODUCTION 240
2. MECHANISM OF ACTION 241
2.1. Transport Over the Cell Membrane 241
2.2. Phosphorylation of Gemcitabine 242
2.3. Accumulation of Triphosphates and Incorporation Into DNA and Ribonucleic Acid 247
2.4. Intracellular Targets 248
2.5. Incorporation Into DNA and RNA 252
2.6. Induction of Apoptosis 253
3. GENOMIC ALTERATIONS AND SENSITIVITY 255
4. DRUG COMBINATIONS 255
5. FUTURE PROSPECTS 256
REFERENCES 257
Clinical Activity of Gemcitabine as a Single Agent and in Combination 267
1. INTRODUCTION 268
2. SINGLE-AGENT EFFICACY 268
2.1. Mechanism of Action 270
2.2. Pharmacology 273
2.3. Toxicity 275
3. GEMCITABINE COMBINATIONS: MECHANISMS OF ACTION 275
3.1. Gemcitabine-Cisplatin 275
3.2. Gemcitabine-Paclitaxel 276
3.3. Other Combinations With Gemcitabine 277
4. GEMCITABINE COMBINATIONS: FIRST- LINE EFFICACY 277
4.1. Advanced NSCLC 277
4.2. Pancreatic Cancer 281
4.3. Advanced Bladder Cancer 282
4.4. Advanced Gastric and Esophageal Cancer 283
4.5. Breast Cancer 283
4.6. Ovarian Cancer 287
5. CONCLUSIONS 289
REFERENCES 290
Nucleoside Radiosensitizers 303
1. INTRODUCTION 305
2. BrdUrd AND IdUrd 306
2.1. Metabolic Considerations 307
2.2. Mechanisms of Radiosensitization 307
2.3. Clinical Aspects 310
3. 5-FU AND FdUrd 311
3.1. Metabolic Considerations 311
3.2. Mechanisms of Radiosensitization 313
3.3. Clinical Aspects 315
4. GEMCITABINE 315
4.1. Metabolic Considerations 316
4.2. Mechanisms of Radiosensitization 317
4.3. Clinical Considerations 320
5. FLUDARABINE 321
5.1. Metabolic Considerations 322
5.2. Mechanism of Radiosensitization 322
5.3. Clinical Considerations 323
6. FLUOROMETHYLENEDEOXYCYTIDINE 323
7. HYDROXYUREA 324
7.1. Metabolic Considerations 325
7.2. Mechanism of Radiosensitization 325
7.3. Clinical Considerations 326
8. CONCLUDING REMARKS 326
REFERENCES 328
NONMEM Population Models of Cytosine Arabinoside and Fludarabine Phosphate in Pediatric Patients With Leukemia 345
1. INTRODUCTION 346
2. MAJOR NONMEM TASKS 347
3. POPULATION PHARMACOKINETIC ANALYSIS OF CYTOSINE ARABINOSIDE 348
4. CYTOSINE ARABINOSIDE 350
5. NONMEM PK MODEL CHARACTERISTICS 350
6. STATISTICAL MODELS FOR ara-C AND ara-U NONMEM POPULATION ANALYSES 352
6.1. NONMEM Analyses of ara-C (Model I) 353
6.2. NONMEM Population PK Analyses of ara-C/ara-U Data ( Model II) 355
7. FLUDARABINE PHOSPHATE NONMEM POPULATION PK- PD ANALYSES IN PEDIATRIC PATIENTS WITH LEUKEMIAS 356
8. NONMEM POPULATION PHARMACOKINETICS MODELING OF F-ara-A AND F-araATP 358
9. DISCUSSION 363
REFERENCES 364
APPENDIX: NONMEM: GUIDELINES TO GET STARTED 365
The cycloSal-Nucleotide Delivery System 367
1. INTRODUCTION 368
2. THE cycloSALIGENYL-PRONUCLEOTIDE APPROACH: THE FIRST GENERATION 370
2.1. CycloSaligenyl-Nucleotides (cycloSal-Nucleoside Monophosphates): The Design of a Concept 370
2.2. Chemistry 374
2.3. Proof of Principle 376
2.5. Application of the cycloSal-Pronucleotides Against DNA Viruses 393
2.4. CycloSal-Pronucleotides of Different Nucleoside Analogs 383
2.5. Application of the cycloSal-Pronucleotides Against DNA Viruses 393
2.6. Interaction of cycloSal-Phosphate Triesters With Human AChE and BChE 401
3. SECOND-GENERATION cycloSAL-PHOSPHATE TRIESTERS 404
3.1. “Lock-in” 404
3.2. Proof of the Lock-In Concept 405
3.3. Antiviral Activity 408
4. CONCLUSION 409
ACKNOWLEDGMENT 410
REFERENCES AND NOTE 410
Purine and Pyrimidine-Based Analogs and Suicide Gene Therapy 417
1. INTRODUCTION 418
2. SUICIDE GENE SYSTEMS 419
2.1. Prodrugs 420
2.2. Suicide Genes 422
2.3. Bystander Effect 439
3. GENE DELIVERY AND TARGETING 441
4. CHALLENGES AND FUTURE ASPECTS 443
REFERENCES 444
3'- Deoxy- 3'- Fluorothymidine as a Tracer of Proliferation in Positron Emission Tomography 455
1. INTRODUCTION 456
2. 3'- DEOXY-3'- FLUOROTHYMIDINE 458
2.1. Synthesis 458
2.2. Pathway 459
2.3. Metabolism 461
2.4. Thymidine Kinases and the Cell Cycle 463
3. APPLICATIONS 464
3.1. Oncology 464
3.2. Response Monitoring 466
4. PET IMAGING 468
4.1. Imaging and Kinetic Model 468
4.2. Safety and Toxicity 469
4.3. Biomarkers 470
5. SUMMARY AND CONCLUSIONS 470
REFERENCES 471
Index 477

Textauszug

6 Cytosine Arabinoside (p. 119-120)

Metabolism, Mechanisms of Resistance, and Clinical Pharmacology

Isabelle Hubeek, PhD,
Gert-Jan L. Kaspers, MD, PhD,
Gert J. Ossenkoppele, MD, PhD,
and Godefridus J. Peters, PhD

CONTENTS

INTRODUCTION
MECHANISMS OF ACTION AND RESISTANCE
ARA-C-MEDIATED CYTOTOXICITY
CLINICAL PHARMACOLOGY OF ARA-C
ANTILEUKEMIC ACTIVITY OF ARA-C
ARA-C COMBINATIONS
ARA-C PRODRUGS
CONCLUSIONS AND FUTURE PERSPECTIVES
REFERENCES

SUMMARY

The deoxynucleoside analog cytarabine (ara-C) remains one of the most effective drugs used in the treatment of acute leukemia as well as other hematopoietic malignancies. The activity of ara-C depends on the conversion to its cytotoxic triphosphate derivative, ara-CTP. This process is influenced by multiple factors, including transport, phosphorylation, deamination, and levels of competing metabolites, deoxycytidine triphosphate in particular. Furthermore, the efficacy of ara-C is determined by the ability of ara-CTP to interfere with deoxyribonucleic acid (DNA) polymerases in the extent of incorporation into the DNA, leading to chain termination. Finally, several factors in the apoptotic pathway also determine sensitivity to ara-C. Ara-C has been given intravenously over a wide range of doses. The standard or conventional dose varies from 100 to 200 mg/m2 daily and is given by intermittent injection or by continuous infusion over 5–10 d. The presence of drug refractoriness and relapsing leukemia together with insights into the mechanisms of ara-C resistance led to the development of high-dose (1–3 g/m2) ara-C treatment. A number of different strategies have been developed to increase the efficacy of ara-C. First, biochemical modulation of ara-C-mediated cytotoxicity, in which ara-C is combined with compounds that enhance its metabolism or interfere with its catabolism, has been successful. Second, ara-C has been encapsulated into multivesicular liposomes, and several ara-C prodrugs containing lipophilic side chains in the base or in the sugar moiety have been designed to increase cellular uptake of ara-C and delay its deamination and clearance. Greater understanding of the metabolism and mechanisms of action of ara-C could contribute to the development of novel therapeutic strategies capable of overcoming ara-C resistance and is essential to improve therapeutic efficacy.

Key Words: Acute myeloid leukemia, biochemical modulation, cytarabine, cytosine arabinoside, deoxycytidine kinase, high-dose ara-C, FLAG, fludarabine.

Produkt-Details

• Erscheint lt. Verlag: 7.11.2007
• Reihe/Serie: Cancer Drug Discovery and Development
• Zusatzinfo: XIV, 476 p.
• Verlagsort: Totowa
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Medizin / Pharmazie ► Studium
• Schlagworte: Cancer • Cancer Therapy • Cell • Chemotherapy • Drug • drug discovery • gene therapy • HIV • Kinetics • leukemia • Metabolism • Oncogenes • Pancreatic cancer • Pharmacokinetics • Research
• ISBN-10: 1-59745-148-7 / 1597451487
• ISBN-13: 978-1-59745-148-2 / 9781597451482