Metronomic Chemotherapy : Pharmacology and Clinical Applications

Annotation This book analyzes all aspects of metronomic chemotherapy, a new approach involving low-dose, long-term, and frequently administered therapy that has preclinical and clinical activity in various tumors. After an opening section on the pharmacological bases of metronomic chemotherapy, including its antiangiogenic effects and impact on immunity, preclinical studies on various classes of drug are discussed. Clinical applications of metronomic chemotherapy in a wide variety of tumors are then addressed in detail, with description of the results of all published studies. The clinical pharmacology of metronomic chemotherapy is also considered in depth, encompassing pharmacokinetics, pharmacogenetics, pharmacoeconomics, and adverse drug reactions. The book closes by describing the role of this therapy in the veterinarian clinic Front Matter....Pages i-xvi Front Matter....Pages 1-1 Development and Evolution of the Concept of Metronomic Chemotherapy: A Personal Perspective....Pages 3-21 Mechanisms of Action of Low-Dose Metronomic Chemotherapy....Pages 23-38 Effects of Metronomic Chemotherapy on Immunity....Pages 39-51 Preclinical Activity of Metronomic Regimens with Alkylating Agents and Antimetabolites....Pages 53-67 Metronomic Chemotherapy Regimens Using Microtubule-Targeting Agents: Mechanisms of Action, Preclinical Activity and Future Developments....Pages 69-90 Front Matter....Pages 91-91 Metronomic Chemotherapy in Breast Cancers....Pages 93-110 Overview of Metronomic Chemotherapy in SWOG Breast Cancer Cooperative Group Clinical Trials....Pages 111-118 Clinical Trials of Low-Dose Metronomic Chemotherapy in Castration-Resistant Prostate Cancer....Pages 119-134 The Role of Metronomic Chemotherapy in the Treatment of Metastatic Colorectal Cancer Patients....Pages 135-142 Clinical Activity of Metronomic Chemotherapy in Central Nervous System Cancers....Pages 143-155 Metronomic Chemotherapy in Pediatric Malignancies....Pages 157-172 Metronomic Chemotherapy in Hematological Malignancies....Pages 173-188 Clinical Activity of Metronomic Chemotherapy in Liver Cancers....Pages 189-202 Metronomic Chemotherapy in Gynecological Cancers....Pages 203-216 Metronomic Chemotherapy in Non-Small-Cell Lung Cancer....Pages 217-226 Front Matter....Pages 227-227 Pharmacokinetics and Pharmacogenetics of Metronomic Chemotherapy....Pages 229-246 Metronomics: Potential Social Impact and New Business Models to Improve Availability of Cancer Treatments....Pages 247-261 Adverse Side Effects Associated with the Use of Low-Dose Metronomic Chemotherapy....Pages 263-279 Front Matter....Pages 281-281 Clinical Studies of Metronomic Chemotherapy in Dogs....Pages 283-295 This book analyzes all aspects of metronomic chemotherapy, a new approach involving low-dose, long-term, and frequently administered therapy that has preclinical and clinical activity in various tumors. After an opening section on the pharmacological bases of metronomic chemotherapy, including its antiangiogenic effects and impact on immunity, preclinical studies on various classes of drug are discussed. Clinical applications of metronomic chemotherapy in a wide variety of tumors are then addressed in detail, with description of the results of all published studies. The clinical pharmacology of metronomic chemotherapy is also considered in depth, encompassing pharmacokinetics, pharmacogenetics, pharmacoenconomics, and adverse drug reactions. The book closes by describing the role of this therapy in the veterinarian clinic 5.2.1 Effects of MTAs on the Microtubule Network of Vascular Endothelial Cells5.2.2 Additional Mechanisms; 5.3 Beyond Angiogenesis Inhibition; 5.4 Preclinical Studies; 5.4.1 Metronomic MTAs in Combination with Targeted Agents; 5.4.2 Metronomic MTAs and Immunotherapy; 5.5 Future Developments; 5.5.1 New MTAs; 5.5.2 New Drug Formulations; Conclusions; References; Part II: Clinical Activity of Metronomic Chemotherapy; 6: Metronomic Chemotherapy in Breast Cancers; 6.1 Introduction; 6.1.1 Breast Cancer Is Not One Disease: Subtypes and Heterogeneity; 6.1.2 The Role of Metronomic Chemotherapy 2.2.1 Low-Dose Metronomic Chemotherapy Directly Kills Endothelial Cells2.2.2 Low-Dose Metronomic Chemotherapy Alters the Expression of Angiogenesis-Related Factors; 2.2.3 Low-Dose Metronomic Chemotherapy Blocks Systemic Angiogenesis; 2.3 Additional Antitumor Activity Mechanisms of Low-Dose Metronomic Chemotherapy; 2.3.1 Low-Dose Metronomic Chemotherapy Enhances the Antitumor Activity of Oncolytic Virotherapy; 2.3.2 Low-Dose Metronomic Chemotherapy Prevents Host Effects Seen in Response to Acute Therapy; 2.3.3 Low-Dose Metronomic Chemotherapy May Disrupt the Cancer Stem Cell's Niche 2.4 SummaryReferences; 3: Effects of Metronomic Chemotherapy on Immunity; 3.1 Introduction; 3.2 The Importance of Antitumor Immunity in Controlling Tumor Growth After Chemotherapy; 3.3 Immunosuppressive Cells in Tumor-Bearing Hosts; 3.4 Effect of Chemotherapeutic Agents on Immune Cells; 3.4.1 Treg Cells; 3.4.2 MDSCs; 3.4.3 DCs; 3.4.4 Others; 3.5 Effects of Metronomic Chemotherapy on Immunity; 3.6 Metronomic/Intermittent Chemotherapy with Low-Dose CTX and GEM; 3.7 Influence of the Administration Schedule on Antitumor T Cell Responses; Conclusions; References 4: Preclinical Activity of Metronomic Regimens with Alkylating Agents and Antimetabolites4.1 Alkylating Agents; 4.1.1 Cyclophosphamide; 4.1.2 Temozolomide (TMZ); 4.2 Antimetabolites; 4.2.1 Gemcitabine (Gemcitabine HCl); 4.2.2 Fluorouracil (5-FU); 4.2.3 Tegafur-Uracil (UFT); 4.2.4 Capecitabine; 4.3 Concluding Remarks; References; 5: Metronomic Chemotherapy Regimens Using Microtubule-Targeting Agents: Mechanisms of Action, Preclinical Activity and Future Developments; 5.1 Introduction; 5.2 Molecular Insights into the Anti-vascular Properties of MTAs Preface; Contents; Contributors; Part I: Pharmacological Bases of Metronomic Chemotherapy; 1: Development and Evolution of the Concept of Metronomic Chemotherapy: A Personal Perspective; 1.1 That Was Then. What Happened Next, and What About Now?; 1.2 Some of the Questions and Challenges That Lie Ahead for More Common Adoption of Metronomic Chemotherapy Concept; 1.3 Summary; References; 2: Mechanisms of Action of Low-Dose Metronomic Chemotherapy; 2.1 Introduction; 2.2 The Antiangiogenic Effects of Low-Dose Metronomic Chemotherapy 6.2 Metronomic Regimens in Breast Cancer: Early Trials