Rethinking Platinum Anticancer Drug Design Towards Targeted And Immuno Chemotherapeutic Approaches

This thesis describes the authors’ pioneering efforts in the conceptualization and implementation of combined platinum-based immuno-chemotherapeutics, which represent a significant paradigm shift from the conventional approach of directly targeting cancer. The work described has opened up a rich and largely unexplored area for platinum-based drug design, and ultimately paves the way for superior immuno-chemotherapeutics with better clinical outcome for patients. Historically, the contribution of the immune system to chemotherapy outcomes has been neglected, as anticancer drugs were believed to be immunosuppressive. However, this has been challenged by contemporary evidence suggesting that many chemotherapeutics, including platinum-based agents, stimulate the innate and/or adaptive immune system and that these “secret allies” contribute tangibly to clinical outcomes. A multi-pronged immuno-chemotherapeutic approach not only shrinks tumors, but more importantly, reactivate dormant immune responses to malignancies, eliminating residual cancer cells.

GLOBAL EPIDEMIOLOGY OF CANCER Cancer is the second highest cause of death in the United States, and a leading cause of death globally. Our goals are to discuss the global epidemiology of various cancers, with detailed information on their prevalence, incidence, and clinical considerations. Epidemiology is the key to understanding the mortality and morbidity of cancer, and how we can prevent, diagnose, and treat the disease. Prevention of cancer is essential for saving lives. Prevalence and incidence of cancer are key factors that each government and population must be aware of. Advances in the study of cancer occur on a regular basis, and this book provides the latest insights about relationships between the disease and stem cells, tumorigenesis, molecular interactions, pathways, channels, and immunity. Global Epidemiology of Cancer: Diagnosis and Treatment meets the needs of readers by providing current information about epidemiology (including molecular epidemiology), diagnosis, and treatment. Providing logical, step-by-step information on various cancers, this book consolidates all of the most up-to-date information and data from verified studies on all different types of cancers in the United States and throughout the world. Chapters are presented so that each includes an overview, clinical manifestations, epidemiology, pathophysiology, etiology and risk factors, diagnosis, treatment, prevention, and prognosis. Global Epidemiology of Cancer: Diagnosis and Treatment will be invaluable to graduate and postgraduate students, including medical students; nurses; physician assistants; residents in oncology; public health students and allied health students.

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.

Nearly a century of scientific research has revealed that mitochondrial dysfunction is one of the most common and consistent phenotypes of cancer cells. A number of notable differences in the mitochondria of normal and cancer cells have been described. These include differences in mitochondrial metabolic activity, molecular composition of mitochondria and mtDNA sequence, as well as in alteration of nuclear genes encoding mitochondrial proteins. This book, Mitochondria and Cancer, edited by Keshav K. Singh and Leslie C. Costello, presents thorough analyses of mitochondrial dysfunction as one of the hallmarks of cancer, discusses the clinical implications of mitochondrial defects in cancer, and as unique cellular targets for novel and selective anti-cancer therapy.

Leading experts summarize and synthesize the latest discoveries concerning the changes that occur in tumor cells as they develop resistance to anticancer drugs, and suggest new approaches to preventing and overcoming it. The authors review physiological resistance based upon tumor architecture, cellular resistance based on drug transport, epigenetic changes that neutralize or bypass drug cytotoxicity, and genetic changes that alter drug target molecules by decreasing or eliminating drug binding and efficacy. Highlights include new insights into resistance to antiangiogenic therapies, oncogenes and tumor suppressor genes in therapeutic resistance, cancer stem cells, and the development of more effective therapies. There are also new findings on tumor immune escape mechanisms, gene amplification in drug resistance, the molecular determinants of multidrug resistance, and resistance to taxanes and Herceptin.

Kinase drug discovery remains an area of significant interest across academia and in the pharmaceutical industry. There are now around 13 FDA approved small molecule drugs which target kinases and many more compounds in various stages of clinical development. Although there have been a number of reviews/publications on kinase research, this book fills a gap in the literature by considering the current and future opportunities and challenges in targeting this important family of enzymes. The book is forward-looking and identifies a number of hot topics and key areas for kinase drug discovery over the coming years. It includes contributions from highly respected authors with a combined experience in the industry of well over 200 years, which has resulted in a book of great interest to the kinase field and across drug discovery more generally. Readers will gain a real insight into the huge challenges and opportunities which this target class has presented drug discovery scientists. The many chapters cover a wide breadth of topics, are well written and include high quality colour and black and white images. Topics covered include an outline of how medicinal chemistry has been able to specifically exploit this unique target class, along with reflections on the mechanisms of kinases inhibitors. Also covered is resistance to kinase inhibitors caused by amino acid mutations, case studies of kinase programs and reviews areas beyond protein kinases and beyond the human kinome. Also described are modern approaches to finding kinase leads and the book finishes with a reflection of how kinase drug discovery may progress over the coming years.

This book presents various computer-aided drug discovery methods for the design and development of ligand and structure-based drug molecules. A wide variety of computational approaches are now being used in various stages of drug discovery and development, as well as in clinical studies. Yet, despite the rapid advances in computer software and hardware, combined with the exponential growth in the available biological information, there are many challenges that still need to be addressed, as this book shows. In turn, it shares valuable insights into receptor-ligand interactions in connection with various biological functions and human diseases. The book discusses a wide range of phylogenetic methods and highlights the applications of Molecular Dynamics Simulation in the drug discovery process. It also explores the application of quantum mechanics in order to provide better accuracy when calculating protein-ligand binding interactions and predicting binding affinities. In closing, the book provides illustrative descriptions of major challenges associated with computer-aided drug discovery for the development of therapeutic drugs. Given its scope, it offers a valuable asset for life sciences researchers, medicinal chemists and bioinformaticians looking for the latest information on computer-aided methodologies for drug development, together with their applications in drug discovery.

In the past decade, we have experienced an explosion of new information about cancer therapeutic targets. Many of the targets have been validated by the discovery and approval of new medicines which have been approved for the treatment of cancer. On the heels of these successes, innumerable new targets and new potential therapeutics are being developed by many different groups including government agencies, pharmaceutical companies, biotechnology companies, academic institutions, and individual investigators. Understanding the expanding "universe" of cancer therapies is therefore becoming impossible and no single source exists which serves as a reference for the involved parties. Further, the interested parties have vastly different areas of expertise, from focused laboratory based science, to clinical research, to corporate and regulatory oversight. The text would be updated every two years, more often depending on pace of change, interest and sales. While useful online, this reference book would likely be kept in hard copy as well.