Martens Small Molecules in Oncology

1. Auflage 2010
ISBN: 978-3-642-01222-8
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 184, 238 Seiten

Reihe: Recent Results in Cancer Research

Extensive research into the molecular mechanisms of cancer disease has heralded a new age of targeted therapy. In malignant cells, key proteins that are crucial to tumor growth and survival are now being targeted directly with rationally designed inhibitors. Apart from monoclonal antibodies, small molecule therapeutics such as oncogenic protein kinase inhibitors are attracting a vast amount of investigational attention. This textbook, written by acknowledged experts, provides a broad overview of the small molecules currently used for the treatment of malignant diseases and discusses interesting novel compounds that are in the process of clinical development to combat cancer.

Autoren/Hrsg.

Martens, Uwe M.

Inhaltsverzeichnis

1;Recent Results in Cancer Research;1
1.1;Protein Kinase Inhibitors;15
1.1.1;Imatinib Mesylate;16
1.1.1.1;Introduction;16
1.1.1.2;Chemical Structure;18
1.1.1.3;Clinical Pharmacology;19
1.1.1.4;Drug Targets;19
1.1.1.5;Preclinical Studies;19
1.1.1.6;Clinical Data in CML;21
1.1.1.6.1;Phase I Trials;21
1.1.1.6.2;Phase II Studies;21
1.1.1.6.3;Phase III Study (IRIS-Trial);22
1.1.1.6.4;Side Effects/Toxicity;23
1.1.1.7;Disease Progression and Imatinib Resistance;24
1.1.1.8;Treatment Recommendations for the Use of Imatinib in Chronic Phase CML;27
1.1.1.9;Imatinib in Combination with Other Drugs;28
1.1.1.10;Imatinib – Other Targets;28
1.1.1.11;Conclusion and Future Perspectives;29
1.1.2;References;30
1.1.3;Erlotinib;34
1.1.3.1;Introduction;34
1.1.3.2;Mechanism of Action;35
1.1.3.3;Non-Small Cell Lung Cancer;35
1.1.3.4;Pancreatic Adenocarcinoma;37
1.1.3.5;Hepatocellular Carcinoma;40
1.1.3.6;Other Tumour Entities;41
1.1.4;References;41
1.1.5;Axitinib (AG-013736);45
1.1.5.1;Introduction;45
1.1.5.2;Structure of Molecule;46
1.1.5.3;Preclinical Data;46
1.1.5.3.1;Bioavailability in Humans;48
1.1.5.4;Phase II Studies;48
1.1.5.4.1;3.4.1Axitinib in Renal Cell Carcinoma;48
1.1.5.4.2;Axitinib in Pancreatic Cancer;49
1.1.5.4.3;Axitinib in Metastatic Breast Cancer;50
1.1.5.4.4;Axitinib in Thyroid Cancer;50
1.1.5.4.5;Axitinib in Other Solid Tumors;51
1.1.5.5;Phase III Studies;51
1.1.5.6;Toxicity;52
1.1.5.7;Drug Interactions;53
1.1.5.8;Future;54
1.1.6;References;54
1.1.7;Lapatinib;57
1.1.7.1;4.1.Introduction;57
1.1.7.1.1;4.1.1.The Epidermal Growth Factor Receptor Family of Tyrosine Kinases;57
1.1.7.1.2;4.1.2.Human Epidermal Growth Factor Receptors and Breast Cancer;59
1.1.7.2;4.2.Structure and Mechanism of Action;59
1.1.7.3;4.3.Clinical Data;61
1.1.7.3.1;4.3.1.Pharmacology;61
1.1.7.3.2;4.3.2.Results from Clinical Trials;61
1.1.7.3.2.1;4.3.2.1.Efficacy;61
1.1.7.3.2.2;4.3.2.2.Tolerability;66
1.1.7.4;4.4.Conclusion and Future Perspectives;66
1.1.8;References;67
1.1.9;Sorafenib;72
1.1.9.1;5.1.Introduction;72
1.1.9.2;5.2.Structure and Mechanism of Action;73
1.1.9.3;5.3.Clinical Data;75
1.1.9.3.1;5.3.1.Phase I;75
1.1.9.3.2;5.3.2.Sorafenib in the Treatment of Renal Cell Cancer (RCC);75
1.1.9.3.3;5.3.3.Sorafenib in the Treatment of Lung Cancer;77
1.1.9.3.4;5.3.4.Sorafenib in the Treatment of Hepatocellular Cancer (HCC);77
1.1.9.3.5;5.3.5.Sorafenib in the Treatment of Breast Cancer;77
1.1.9.3.6;5.3.6.Sorafenib in the Treatment of Malignant Melanoma;77
1.1.9.3.7;5.3.7.Sorafenib in the Treatment of Prostate Cancer;78
1.1.9.3.8;5.3.8.Sorafenib in the Treatment of Head and Neck Cancer;78
1.1.9.3.9;5.3.9.Sorafenib in the Treatment of Ovarian Cancer;78
1.1.9.3.10;5.3.10.Sorafenib in the Treatment of Brain Tumors;78
1.1.9.3.11;5.3.11.Sorafenib in the Treatment of Thyroid Cancer;78
1.1.9.3.12;5.3.12.Sorafenib in the Treatment of Hematologic Diseases;78
1.1.9.4;5.4.Conclusion and Future Perspectives;79
1.1.10;References;79
1.1.11;Sunitinib;82
1.1.11.1;Introduction;82
1.1.11.2;Sunitinib;82
1.1.11.3;Renal Cell Carcinoma;83
1.1.11.3.1;6.3.1Targets for Renal Cell Carcinoma;83
1.1.11.3.2;Phase II/III Studies in Metastatic RCC;85
1.1.11.4;Gastrointestinal Stromal Tumors;86
1.1.11.4.1;Targets for Gastrointestinal Stromal Tumors;86
1.1.11.4.2;GIST Clinical Trials;86
1.1.11.4.3;Side Effects;87
1.1.11.4.4;Drug Interactions;89
1.1.11.4.5;Activity in Other Tumor Sites and Ongoing Research;89
1.1.11.5;Conclusion;90
1.1.12;References;90
1.1.13;Dasatinib;94
1.1.13.1;Introduction;94
1.1.13.2;Structure and Mechanism of Action;96
1.1.13.2.1;Inhibition of ABL;97
1.1.13.2.2;Inhibition of SRC;98
1.1.13.2.3;Inhibition of c-KIT;98
1.1.13.2.4;Inhibition of Platelet-Derived Growth Factor Receptor (PDGFR)-.a. and .b. Tyrosine Kinases;99
1.1.13.2.5;Inhibition of Ephrin Receptor Tyrosine Kinases;99
1.1.13.2.6;Additional Effects;99
1.1.13.3;Clinical Data;99
1.1.13.3.1;Pharmacokinetic Profile;99
1.1.13.3.2;Clinical Studies with Dasatinib in CML and Other Diseases;100
1.1.13.3.3;CML and Ph.+. ALL – Overview;100
1.1.13.3.3.1;Phase I Dose Escalation Study;100
1.1.13.3.3.2;Phase II: Chronic Phase CML (START C);101
1.1.13.3.3.3;Accelerated Phase CML (START A);101
1.1.13.3.3.4;Myeloid Blast Phase CML (START B) and Lymphatic Blast Phase CML (START L);101
1.1.13.3.3.5;Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (ALL);103
1.1.13.3.3.6;Central Nervous System Disease of Ph.+. Blast Phase CML or Ph.+. ALL;103
1.1.13.3.3.7;Randomized Comparison of Dasatinib vs. High-Dose Imatinib (START R);103
1.1.13.3.3.8;Dasatinib in Previously Untreated Chronic Myelogenous Leukemia Patients;104
1.1.13.3.3.9;Dose Optimization Trial in Chronic Phase CML;104
1.1.13.3.3.10;Dose Optimization Phase III Trial in Advanced Phase CML;105
1.1.13.3.4;Dasatinib and Other Diseases;106
1.1.13.3.4.1;Phase I Study in GIST;106
1.1.13.3.4.2;Phase I Study in Solid Tumors;106
1.1.13.3.4.3;Phase II Study of Dasatinib in Philadelphia Chromosome Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocy;106
1.1.13.3.4.4;Phase II Study with Dasatinib in Patients with Hormone Refractory Progressive Prostate Cancer;107
1.1.13.3.5;Safety and Tolerability;107
1.1.13.3.5.1;Hematological Toxicity;107
1.1.13.3.5.2;Fluid Retention;107
1.1.13.3.5.3;Bleeding;109
1.1.13.3.5.4;QT-Prolongation;109
1.1.13.4;Conclusion and Further Perspectives;109
1.1.14;References;110
1.1.15;Nilotinib;114
1.1.15.1;Background;114
1.1.15.2;Preclinical and Pharmacokinetic Data;115
1.1.15.2.1;Pharmacological Design;115
1.1.15.2.2;Drug Targets;115
1.1.15.2.3;Preclinical Activity;115
1.1.15.2.4;Pharmacokinetics and Metabolism;116
1.1.15.3;Clinical Efficacy;116
1.1.15.3.1;Nilotinib Phase I Study;117
1.1.15.3.2;Nilotinib After Imatinib Failure;117
1.1.15.3.3;Nilotinib First-Line Therapy;119
1.1.15.3.4;Nilotinib After Dasatinib Failure;119
1.1.15.3.5;Toxicity;120
1.1.15.3.6;Resistance to Nilotinib;123
1.1.15.4;Outlook;124
1.1.15.5;Conclusion;125
1.1.16;References;125
1.1.17;Bosutinib;129
1.1.17.1;Chemical Structure;129
1.1.17.2;Mechanism of Action;129
1.1.17.2.1;SRC Kinase Inhibition;130
1.1.17.2.2;Abl and bcr-abl Inhibition;130
1.1.17.3;Bosutinib in Chronic Myeloid Leukaemia (CML);131
1.1.17.3.1;Preclinical Data;131
1.1.17.3.2;Clinical Trials;131
1.1.17.3.2.1;CML Chronic Phase (CP CML);131
1.1.17.3.2.2;Accelerated Phase (AP CML), Blast Phase (BP CML) and Ph.+. ALL;132
1.1.17.4;Bosutinib in Solid Tumours;134
1.1.17.4.1;Preclinical Data;134
1.1.17.4.1.1;Breast Cancer;134
1.1.17.4.1.2;Colorectal Cancer;134
1.1.17.4.1.3;Non-Small Cell Lung Cell Cancer (NSCLC);134
1.1.17.4.2;Clinical Trials;135
1.1.17.5;Conclusion and Future Directions;135
1.1.18;References;136
1.2;Epigenetic Modifiers;138
1.2.1;Decitabine;139
1.2.1.1;Introduction;139
1.2.1.2;Structure and Mechanism of Action;140
1.2.1.3;Studies of Single-Agent Decitabine in MDS and Acute Leukemias;141
1.2.1.4;Combination Treatment in AML, MDS, and Other Diseases;143
1.2.1.5;Decitabine as a Preparative Agent in Allogeneic Stem Cell Transplantation;148
1.2.1.6;Immunomodulation with Decitabine;150
1.2.1.7;Decitabine Treatment in Other Diseases;151
1.2.1.7.1;Activity of Decitabine in Patients with Acute Lymphoblastic Leukemia;151
1.2.1.7.2;Activity of Decitabine in Patients with Chronic Myeloid Leukemia;152
1.2.1.7.3;Activity of Decitabine in Patients with Idiopathic Myelofibrosis (IMF);153
1.2.1.7.4;Clinical Effects of Decitabine in Severe .b.-Thalassemia and Sickle Cell Disease;153
1.2.1.7.5;Efficacy of Decitabine in Patients with Solid Tumors;154
1.2.1.8;Conclusion and Future Perspectives;156
1.2.2;References;157
1.2.3;5-Azacytidine/Azacitidine;166
1.2.3.1;Introduction...: 5-Azacytidine – Novel or Almost Historic?;166
1.2.3.2;Agent;167
1.2.3.2.1;Chemical Structure;167
1.2.3.2.2;Mode of Action;167
1.2.3.3;Pharmacology;168
1.2.3.3.1;Route of Administration and Dosage;168
1.2.3.3.2;Bioavailability, Half-Life, Elimination, Drug–Drug Interactions;169
1.2.3.3.3;Safety, Side Effects, and Contraindications;169
1.2.3.3.3.1;Hematologic Toxicity/Myelosuppression;169
1.2.3.3.3.2;Gastrointestinal Toxicity;170
1.2.3.3.3.3;Hepatotoxicity;170
1.2.3.3.3.4;Nephrotoxicity;170
1.2.3.3.3.5;Other;170
1.2.3.3.3.6;Teratogenicity;170
1.2.3.4;Clinical Use of 5-Azacytidine;171
1.2.3.4.1;Early Studies;171
1.2.3.4.2;5-Azacytidine in Myelodysplastic Syndromes (MDS);171
1.2.3.4.3;New Therapeutic Approaches;173
1.2.3.5;Future Perspective, Experimental Studies, and Conclusion;173
1.2.4;References;174
1.3;Cell Cycle Inhibitors;178
1.3.1;Bortezomib;179
1.3.1.1;Mode of Action;179
1.3.1.2;Antitumor Effects;181
1.3.1.3;Clinical Application of Proteasome Inhibitors;182
1.3.1.4;Bortezomib;183
1.3.1.5;Bortezomib-Based Combination Therapy for Multiple Myeloma;184
1.3.1.6;Treatment Options for Patients Eligible for Transplant;185
1.3.1.7;Next Generation Proteasome Inhibitors;185
1.3.2;References;186
1.3.3;Temsirolimus;194
1.3.3.1;Introduction;194
1.3.3.2;Development;195
1.3.3.3;Structure and mechanism of action;195
1.3.3.4;Clinical Data;197
1.3.3.5;Safety and Efficacy;197
1.3.3.6;Side Effects;198
1.3.3.7;Conclusion and Future Perspectives;199
1.3.4;References;200
1.3.5;Danusertib (formerly PHA-739358) – A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibit;203
1.3.5.1;Introduction;203
1.3.5.2;Structure, Localization, and Functions;204
1.3.5.3;Aurora Kinases and Cancer;205
1.3.5.4;Inhibitors;206
1.3.5.5;Danusertib (formerly PHA-739358);208
1.3.5.6;Conclusion;212
1.3.6;References;213
1.3.7;BI_2536 - Targeting the Mitotic Kinase Polo-Like Kinase 1 (Plk1);219
1.3.7.1;Introduction;219
1.3.7.2;Structure and Mechanism of Action;221
1.3.7.3;Clinical Data;221
1.3.7.4;Conclusion and Future Perspectives;222
1.3.8;References;222
1.4;Other Novel Agents;223
1.4.1;Imetelstat (GRN163L) -Telomerase-Based Cancer Therapy;224
1.4.1.1;Introduction;224
1.4.1.2;Telomerase-Based Approaches of Cancer Treatment;227
1.4.1.3;Telomerase Inhibition;227
1.4.1.4;Structure of Imetelstat and Mechanism of Action;227
1.4.1.5;Preclinical and Clinical Data of Imetelstat;228
1.4.1.6;Conclusion and Future Prospects;232
1.4.2;References;232
1.4.3;GDC-0449 - Targeting the Hedgehog Signaling Pathway;238
1.4.3.1;Introduction;238
1.4.3.2;Structure and Mechanism of Action;239
1.4.3.3;Clinical Data;239
1.4.3.4;Conclusion and Future Perspectives;240
1.4.4;References;240