Razoxane and Dexrazoxane - Two Multifunctional Agents (eBook)

Experimental and Clinical Results

Walter Rhomberg, Kurt Hellmann (Herausgeber)

eBook Download: PDF

2010 | 2011
XIII, 243 Seiten
Springer Netherland (Verlag)
978-90-481-9168-0 (ISBN)

Infos

Razoxane and dexrazoxane are two novel drugs with some uniquely useful features. They block cell division at the G2/M border, but nowhere else, so that they have a low toxicity profile. They suppress tumor metastasis and haemorrhages through normalization of pathological blood vessels. Razoxane potentiates radiotherapy especially in the treatment of soft tissue sarcomas and gastrointestinal neoplasms. They protect normal tissues against toxic chemicals, e.g. the myocardium against anthracyclines or subcutaneous tissue against injuries caused by incidental extravasations of anthracyclines. Dexrazoxane is the only drug approved by the FDA/EMEA for the specific purpose of preventing cardiac damage when giving the widely used and effective antitumor anthracyclines. The reduction of cardiotoxicity is achieved without response reduction or reducing of time to progression of tumors. While the full analysis of their actions at the molecular level is not yet completely understood, it seems most likely that it is via an inhibition on the topoisomerase II a. Moreover, the drugs have the ability to chelate several metals including iron, copper or zinc. The protection of normal tissues is nowhere more important than that of brain, and there are indications that the proteins thought to be responsible for the ravages of Alzheimer´s disease could be stabilized by one or both these drugs.

Inhalt

Preface 5
Acknowledgments 7
Contents 8
Contributors 11
1 Introduction 12
1.1 Overview and Historical Development of Razoxane and Dexrazoxane 12
1.1.1 History 12
1.1.2 Influence on the Cell Cycle 13
1.1.3 Antimetastatic Activity 14
1.1.4 Cardioprotection (Tissue Protection) 15
1.1.4.1 Pediatric Trials 16
1.1.5 Further Aspects 17
References 17
2 Razoxane 19
2.1 Preclinical Data In Vitro and In Vivo 19
References 20
2.2 Modes of Action: A Brief Summary 21
2.2.1 Effects on the Cell Cycle 21
2.2.2 Normalization of Tumour Blood Vessels 22
2.2.3 Antiinvasive Activity 22
2.2.4 Inhibition of Topoisomerase II 22
2.2.5 Chelation of Metals 23
2.2.6 Cytorallentaric Mode of Action 24
References 24
2.3 Clinical Studies in Malignant Tumors 26
2.3.1 Razoxane (ICRF-159) as Antitumor Agent 26
2.3.1.1 Leukaemias and Malignant Lymphomas 26
2.3.1.2 Solid Tumors, Single Agent Therapy 28
2.3.1.3 Solid Tumors, Multiagent Therapy 32
2.3.1.4 Adjuvant Use of Razoxane 33
References 36
2.3.2 Razoxane as Radiosensitizer 38
2.3.2.1 Soft Tissue-, Osteosarcomas, Chordomas 39
References 41
Reference 46
References 51
References 64
References 74
References 82
2.3.2.2 Gastro-Intestinal Malignancies 84
References 86
References 89
References 94
References 100
2.3.2.3 Lung Cancer 101
2.3.2.4 Other Solid Tumors 102
References 107
2.3.3 Antimetastatic Efficacy of Razoxane 107
2.3.3.1 Preclinical Evidence 107
References 109
2.3.3.2 Metastasis and the Entry of Cancer Cells into the Vasculature -- Prevention by Razoxane 109
References 118
2.3.3.3 Clinical Evidence 120
References 121
References 128
References 133
2.3.4 Razoxane – A Cytorallentaric Drug 133
References 146
2.3.5 Toxicity of Razoxane 148
2.3.5 Razoxane as Single Agent 148
Combined Modality Therapy 150
The Issue of Leukemia-Induction 151
Risk of Secondary Malignant Neoplasms (SMN) 153
The Toxicity of Dexrazoxane: Are There Differences to Razoxane? 153
References 154
2.4 Studies in Non-malignant Diseases 156
2.4.1 Psoriasis and Psoriatic Arthropathy 156
References 160
2.4.2 Crohn's Disease and Ulcerative Colitis 161
References 166
3 Dexrazoxane 167
3.1 Preface 167
3.2 The Pharmacology of Dexrazoxane: Iron Chelating Prodrug and Topoisomerase II Inhibitor 168
3.2.1 Introduction 168
3.2.2 Chemistry of Dexrazoxane 170
3.2.2.1 Biochemistry and Pharmacology of Dexrazoxane 170
3.2.2.2 Pharmacokinetics and Metabolism of Dexrazoxane 171
3.2.2.3 Tests of Other Iron Chelators as Anthracycline Protective Agents 171
3.2.2.4 Dexrazoxane Inhibition of Topoisomerase II 172
3.2.3 Conclusions 174
References 175
3.3 Toxicology and Pharmacokinetics 177
3.3.1 Introduction 177
3.3.2 Single Dose Toxicity 178
3.3.3 Repeated Dose Toxicity 180
3.3.4 Teratogenicity Studies 182
3.3.5 Mutagenicity 183
3.3.6 Carcinogenicity 184
3.3.7 Pharmacodynamics 185
3.3.8 Pharmacokinetics 186
3.3.9 Local Tolerance 187
References 187
3.4 Identification of Dexrazoxane as a Cardioprotector 188
References 191
3.5 Dexrazoxane as Antitumour Agent 191
3.5 Dexrazoxane as Cytotoxic Agent 191
Dexrazoxane as Radiosensitizing Agent 193
Antimetastatic Activity 193
Summary and Comment 193
References 194
3.6 Protection Against Anthracycline-Induced Cardiotoxicity. Clinical Aspects 195
3.6.1 Two Pivotal Studies of Dexrazoxane as Cardioprotector: A Report Including Pharmacology and Safety Issues 195
References 211
3.6.2 Comments on the Definitive Trials of Dexrazoxane Protection against Anthracycline Cardiotoxicity: The Swain Trails 213
References 217
3.6.3 Studies of Dexrazoxane Against the Cardiotoxicity of Anthracyclines in Adult and Paediatric Patients -- An Update 217
References 222
3.7 Non-cardioprotective Efficacy 224
3.7.1 Anthracycline Extravasation 224
3.7.2 Other Possible Indications 229
References 230
3.8 Neurodegenerative Diseases, a Future Avenue for Razoxane and Dexrazoxane Therapeutic Use 232
3.8.1 Background 232
3.8.2 Alzheimer's Disease 233
3.8.3 Parkinson's Disease 234
3.8.4 Metals in AD and PD Brain 235
3.8.5 Chelating Agents in AD and PD 238
References 242
4 Summary and Outlook 246
Outlook 247
Index 250

Produkt-Details

• Erscheint lt. Verlag: 3.8.2010
• Zusatzinfo: XIII, 243 p.
• Verlagsort: Dordrecht
• Sprache: englisch
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Kardiologie / Angiologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Medizinische Fachgebiete ► Radiologie / Bildgebende Verfahren ► Radiologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Humanbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zoologie
• Schlagworte: Radiaton Oncology
• ISBN-10: 90-481-9168-8 / 9048191688
• ISBN-13: 978-90-481-9168-0 / 9789048191680