Cancer Drug Discovery and Development - Böcker

This comprehensive review of existing and potential anticancer drugs and therapies by leading researchers from academia, government laboratories, and pharmaceutical companies offers essential insight into what has been accomplished and where the experimental therapy of cancer is going. The authoritative contributors illuminate the current status of the major molecules of cancer treatment, ranging from the nitrogen mustards through platinum complexes to interferons, cytokines, growth factors and their inhibitors, and on to immunotoxins, antisense oligonucleotides, and gene therapy. A companion volume by the same editor (Anticancer Drug Development Guide: Preclinical and Clinical Screening and Approval) details the processes by which new anticancer drugs are approved. These two volumes in the Cancer Drug Discovery and Development series reveal how and why molecules become anticancer drugs and thus offer a blueprint for the present and the future of the field.

Antifolates are an important class of anticancer drugs originally developed as anti leu- kemic agents, but now used, usually in combination with other drugs, for the treatment of a wide range of tumors, notably carcinomas of the head and neck, breast, germ cell tumors, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and osteogenic sar- comas. 5-Fluorouracil and its prodrugs also target, in part, the folate-dependent enzyme, thymidylate synthase. Furthermore, folate supplementation in the form of leucovorin, modulates 5-fluororuacil activity. 5-Fluorouracil is widely used in the treatment of colorectal and gastric cancer and in combination for other solid tumors such as breast and head and neck cancers. Ongoing clinical trials with the newer antifolates suggest that the range of solid tumors where these agents will be of use may broaden further. Half a century ago, interesting scientific and clinical discoveries suggested that folie acid was a vitamin involved in vital cellular metabolic processes.The folate analogs, aminopterin and methotrexate, were synthesized by the American Cyanamid Company in an attempt to interfere with these processes and were shown to have anticancer activity by Farber and his colleagues. Hence, the principle of antimetabolite therapy for the treatment of cancer was established. Biomedical research over the following years led to a deeper understanding of the complex biochemical pharmacology of folates and antifolates. Selective antimicrobial agents were discovered, but more tumor-selective anticancer agents did not immediately emerge.

Leading international experts comprehensively review all aspects of platinum anticancer drugs and their current use in treatment, as well as examining their future therapeutic prospects. Writing from a variety of disciplines, these authorities discuss the chemistry of cisplatin in aqueous solution, the molecular interaction of platinum drugs with DNA, and such exciting new areas as DNA mismatch repair and replicative bypass, apoptosis, and the transport of platinum drugs into tumor cells. The emergent platinum drugs of the future - orally active agents, the sterically hindered ZD0473, and the polynuclear charged platinum BBR3464 - are also fully considered. Timely and interdisciplinary, Platinum-Based Drugs in Cancer Therapy offers cancer therapeutics specialists an illuminating survey of every aspect of platinum drugs from mechanisms of action to toxicology, tumor resistance, and new analogs.

Cutting-edge researchers describe their efforts to design, synthesize, and evaluate the biological activities of farensyltransferase inhibitors (FTIs); geranylgeranyltransferase inhibitors (GGTIs) are also discussed as potential anticancer drugs. The authors survey in detail such inhibitors as CAAX box peptidomimetics, FPP mimics, and bisubstrate transition state analogs, and critically review their uses in combination with radiation and other cytotoxic agents, such as gemcitabine, cisplatin, and taxanes. Illuminating and richly detailed, Farnesyltransferase Inhibitors in Cancer Therapy constitutes today's standard reference for the pathbreaking use of FTIs and GGTIs in anticancer therapy and offers basic and clinical investigators a comprehensive treatment of the scientific and medical aspects of farnesyltransferase inhibitors.

Cutting-edge investigators review the current status of the entire field, from the biology of MMPs through the current clinical studies. The authors include many leading scientists from pharmaceutical companies who present all the latest concepts and results on the preferred design strategies for MMP inhibitors, their molecular mechanisms, and their substrates. In addition, they fully describe their personal research on specific MMP inhibitors, detailing vanguard design strategies, their in vitro activity, the outcome of animal model studies and, where available, their toxicology, safety, efficacy in human clinical trials. Comprehensive and state-of-the-art, Matrix Metalloproteinase Inhibitors in Cancer Therapy offers basic and clinical investigators alike a richly informative summary of all the latest research on these powerful new drugs, and their high promise as emerging cancer therapeutics.

In Hormone Therapy in Breast and Prostate Cancer, many of today's leading researchers and clinicians describe the principles underlying targeted hormonal treatments, assess the actions of new and established agents, and illustrate the new applications of hormonal chemoprevention for breast cancer. Topics range from preclinical and clinical antiestrogens to the inhibition of estrogen synthesis and the effects of androgen withdrawal. A wide variety of proven and new agents are discussed-antiestrogens, including aromatase inhibitors (anastrozole, letrozole, and others), SERMs (tamoxifen, raloxifene, and others), and such antiandrogenic strategies as goserelin and bicalutamide.

Leading scientists summarize the latest findings on signal transduction and cell cycle regulation and describe the effort to design and synthesize inhibiting molecules, as well as to evaluate their biochemical and biological activities. They review the relevant cell surface receptors, their ligands, and their downstream pathways. Also examined are the latest findings on the components of novel signaling networks controlling the activity of nuclear transcription factors and cell cycle regulatory molecules. Cutting-edge and highly suggestive, Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases presents a wealth of information on the emerging principles of the field, as well as an invaluable guide for all experimental and clinical investigators of cell regulation and its rapidly emerging pharmacological opportunities today.

This collection of thoughtful and provocative articles focused on the key issues in apoptosis, ranges from the role of apoptosis in defining the response of authentic tumor populations to chemotherapeutic agents to the mechanisms coupling DNA damage to the activation pathway of apoptosis. It reviews the profusion of new signaling, modulating, and effector molecules now implicated in apoptosis and whether other routes to "programmed" cell death may exist. Also addressed are the nature of the molecules that will either constitute targets for future drugs or influence the efficacy of current therapies, as well as mechanistic questions on the control of apoptosis. By focusing on essential questions and critically summarizing the overwhelming tide of recent research results, Apoptosis and Cancer Chemotherapy illuminates not only the potential targets for tumor therapy, but beyond that, potential control points for cancer and such diverse diseases as viral infection, neurodegenerative disorders, and stroke. This collection of cutting-edge reviews by established leaders in the field critically summarizes the recent discoveries concerning apoptosis, cell suicide.The book looks forward to the time when such cell death can be controlled to treat cancer and a host of other diseases as diverse as viral infection, neurodegenerative disorders, and stroke.

David Fisher, MD, PhD, and an authoritative panel of academic, cutting-edge researchers review and summarize the current state of the field. Describing the broad roles of tumor suppressors from a perspective based in molecular biology and genetics, the authors detail the major suppressors and the pathways they regulate, including cell cycle progression, stress responses, apoptosis, and responses to DNA damage. Leading-edge and forward-looking, Tumor Suppressor Genes in Human Cancer illuminates what is currently known of tumor suppressor genes and their regulation, work that is already beginning to revolutionize cancer target elucidation, drug discovery, and treatment design.

Cytokines in the Genesis and Treatment of Cancer provides a comprehensive picture of the dual role of host responses in promoting and inhibiting tumor progression. This volume represents an important investigation into the emerging intersection of cancer biology and cancer immunology. Divided into four sections, the volume’s first three parts focus on cytokines in the genesis of cancer. The final section describes the notable progress — both in animal models and humans — in demonstrating the use of cytokine or anticytokine therapies for the prevention and treatment of cancer. Cytokines in the Genesis and Treatment of Cancer brings together an impressive array of internationally distinguished investigators who are devoted to the study of cytokines and cancer. Together, they produce an insightful, comprehensive discussion of cytokines and cancer that will serve as the perfect reference for all those working in the field.

Leading experts survey the currently available technologies designed to improve the delivery of today's cancer chemotherapeutic agents. The authors review both the theoretical and practical considerations governing conventional and nonconventional methods of drug administration, and identify promising opportunities for product development. In their outline and discussion of the use of novel formulation technologies - including synthetic polymers and biomaterials for prolonged or sustained drug release to achieve potentially greater therapeutic effect - they profile those technologies that have resulted in a number of approved and late-stage clinical products.

In Tumor Targeting in Cancer Therapy, Dr. Michel Page and a panel of authoritative experts from the drug industry, clinics, and academia introduce the principles and techniques of tumor targeting and critically survey their applications from laboratory to bedside. By concisely synthesizing the many technical details, the authors illuminate this innovative technique, ranging from the fundamentals of drug targeting and in vivo and in vitro experimentation, to such emerging therapeutic uses as radioimmunotherapy, radioimmunodetection, therapy with cytotoxic antibodies, immunotoxins, enzyme prodrug immunotherapy, and immunotherapeutics with fusion proteins. There are also reviews of targeting tumors with radioimmunoconjugates, photodynamic therapy, and magnetic drugs, as well as discussions of the internalization of antibodies, bioconjugation and biodistribution, the use of cytotoxic drugs, and the pros and cons of targeting by antibody or ligand.

Leading clinicians and investigators review in a comprehensible and user-friendly style all the latest information about the molecular biology of cell cycle control and demonstrate its clinical relevance to understanding neoplastic diseases. Topics range from Cdk inhibitors and cell cycle regulators to the prognostic value of p27 and tumor suppressor genes as diagnostic tools. Actual case studies show how the new molecular understanding has produced such drugs as Flavopiridol and Sulindac. The book brings all the recent critical research findings to bear on clinical practice, and clearly shows their powerful impact on the diagnostics, prognostics, and therapeutics of cancer, AIDS, and cardiovascular disease.

In Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear Proteins, a panel of leading basic researchers, pharmaceutical scientists, and clinical oncologists explain in detail the therapeutically-relevant protein targets that contribute to cancer pathology and spell out their implications for cancer drug discovery and clinical application. The authors identify and illuminate selected transcription factor oncoproteins and tumor suppressors, together with nuclear proteins that are central to the phenotype of the tumor cell involved in chromatin control. The emphasis is on new targets and approaches to cancer treatment derived from the cancer cell cycle, gene control targets, and angiogenesis.

Leading cancer researchers update and review the mechanisms of action and the therapeutic selectivity and efficacy of 5-FU with and without leucovorin and its prodrugs in the treatment of colorectal cancer. Among the combination agents considered are UFT/LV, 5-FU/EU, capecitabine (Xeloda), S-1, and a variety of thymidylate synthase inhibitors. The authors discuss the potential advantages and disadvantages of these varied drugs and their mode of administration. Based on historical results with these agents when used alone, they also present a rationale for their results when used in combination with other agents.

Prominent investigators and clinicians summarize in a balanced blend of fundamental science, basic research, experimental therapeutics, and early clinical experiences, what is known about oncogenes and oncogenesis, and describe how that knowledge can be used to treat the cancer. The contributors explain how, why, and under what conditions certain proteins acquire the ability to transform eukaryotic cells, and detail the crucial biological consequences of this oncogenic transformation, particularly for cellular mitogenesis, survival, differentiation, migration, proteolysis, or angiogenic competence. Their articles thoroughly explicate the premises, principles, techniques, and approaches to oncogene targeting in various types of human cancer by using signal transduction inhibitors, immunological targeting methods, and antisense gene therapy.

In spite of the development of various anticancer drugs, the therapy of cancer has remained challenging for decades. The current therapy of cancer is overwhelmed because of the inability to deliver therapeutics to all regions of a tumor in effective therapeutic concentrations, intrinsic or acquired resistance to the treatment with currently available agents via genetic and epigenetic mechanisms, and toxicity. As a result, cancer therapy using conventional therapeutics and different types of treatment regimens using this therapeutics has not led to a convincing survival benefit of the patients. In this context, Macromolecular therapeutics offer several advantages over conventional low molecular therapeutics by various ways such as, enable the use of larger doses of these agents by limiting the toxicity, by enhanced permeability and retention into tumors, by tumor targeting using tumor-specific antibodies, by specific inhibition of oncogenes using anticancer oligonucleotides etc. Cancer treatment using this macromolecular therapeutics has considerably improved the survival benefit for patients. As a result, various macromolecular therapeutics are already commercialized or are under clinical development. Although we are far from a real magic bullet today, looking at the pace of research and current success in this field of macromolecular therapeutics, it appears that we are approaching a magic bullet for the efficient treatment of cancer. Thus, we believe that the subject of this book is very timely, and that the book will fill an unmet need in the market.This book is unique and assembles various types and aspects of macromolecular anticancer therapeutics for cancer therapy in one shell and conveys the importance of this interdisciplinary field to the broad audience. Thus, in a nutshell, this book details the basics of cancer, and various therapeutic strategies such as those based on macromolecular therapeutics hence can become an important reference for practitioners, oncologists, medical pharmacologists, medicinal chemists, biomedical scientists, experimental pharmacologists, pharmaceutical technologists, and particularly it can essentially become a handbook of macromolecular therapeutics for cancer therapy for graduates, post-graduates and Ph.D. students in these fields.

Nitric Oxide (NO) is a pleitropic, ubiquitous modulator of cellular functions. Aryl nitrite and glyceryl trinitrate, representative intravasadilators, were introduced as therapeutic agents more than a century ago for relief from acute attacks of angina. The vasodilator action is mediated by the release of NO following treatment. NO has important therapeutic applications in several diseases such as inflammatory diseases, erectile dysfunction, inflammation, pain and neural protective activity. However, the role of NO in cancer and its application in therapy has received little attention. This monograph will be the first to focus on studies that investigate the role of NO in tumor cell pathogenesis, growth, angiogenesis, response to cytotoxic therapies and NO translational applications in cancer therapy, alone or in conjunction with other therapies.

The fact that tumors are composed of both tumor cells and host cells has long been known. These tumor-associated cells include vascular endothelial cells and pe- cytes, as well as inflammatory cells such as neutrophils, monocytes, macrophages, mast cells and eosinophils, and lymphocytes. The tumor cells also interact with stromal cells and with elements of the tissue extracellular matrix. What has been less appreciated is the role that these cells could have in modulating the growth, invasion, and metastasis of the tumor. Early on, the elements of what we now call the tumor microenvironment were considered to be more or less innocent bysta- ers to the role of the tumor cells as they grew and invaded local sites. Today, there is an increased understanding of the critical role of the tumor microenvironment as dramatically influencing the course of tumor development and dissemination. This volume represents a superb compilation of the latest thoughts and data regarding the role of each essential component of the tumor microenvironment in cancer development and progression. Perhaps, the earliest recognition of the role of nonmalignant cells as cancer re- lators was the recognition that lymphocytes can participate in what was termed “immune surveillance” in the 1960s. Our understanding of tumor immunity has improved markedly since then, and there are now successful clinical studies sh- ing the potential use of immune-based therapies in cancer treatment.

A practical guide to the design, conduction, analysis and reporting of clinical trials with anticancer drugs.

DNA topoisomerases represent an essential family of DNA processing enzymes and a large number of topoisomerase inhibitors are used clinically for the treatment of various human cancers. Novels drugs are in clinical development both against type I and type II topoisomerases. The book will include basic biochemical and structural reviews for the cancer-relevant topoisomerases. It will describe how topoisomerase dysfunctions can damage the genome and increase the risk of cancers, and the involvement of topoisomerases in programmed cell death. The book will also present the various topoisomerase inhibitors in clinical use and development and their molecular and cellular mechanisms of action.

The book will detail the history, successes, and failures of targeted therapies for cancer, with a particular focus on IGF systems and cancer.

This book will cover primary roles of NKT cells in immunity to cancer, in both mouse tumor models and cancer patients. There are several chapters describing general aspects of NKT cells.

In spite of the development of various anticancer drugs, the therapy of cancer has remained challenging for decades. The current therapy of cancer is overwhelmed because of the inability to deliver therapeutics to all regions of a tumor in effective therapeutic concentrations, intrinsic or acquired resistance to the treatment with currently available agents via genetic and epigenetic mechanisms, and toxicity. As a result, cancer therapy using conventional therapeutics and different types of treatment regimens using this therapeutics has not led to a convincing survival benefit of the patients. In this context, Macromolecular therapeutics offer several advantages over conventional low molecular therapeutics by various ways such as, enable the use of larger doses of these agents by limiting the toxicity, by enhanced permeability and retention into tumors, by tumor targeting using tumor-specific antibodies, by specific inhibition of oncogenes using anticancer oligonucleotides etc. Cancer treatment using this macromolecular therapeutics has considerably improved the survival benefit for patients. As a result, various macromolecular therapeutics are already commercialized or are under clinical development. Although we are far from a real magic bullet today, looking at the pace of research and current success in this field of macromolecular therapeutics, it appears that we are approaching a magic bullet for the efficient treatment of cancer. Thus, we believe that the subject of this book is very timely, and that the book will fill an unmet need in the market.This book is unique and assembles various types and aspects of macromolecular anticancer therapeutics for cancer therapy in one shell and conveys the importance of this interdisciplinary field to the broad audience. Thus, in a nutshell, this book details the basics of cancer, and various therapeutic strategies such as those based on macromolecular therapeutics hence can become an important reference for practitioners, oncologists, medical pharmacologists, medicinal chemists, biomedical scientists, experimental pharmacologists, pharmaceutical technologists, and particularly it can essentially become a handbook of macromolecular therapeutics for cancer therapy for graduates, post-graduates and Ph.D. students in these fields.

This monograph will be the first to focus on studies that investigate the role of NO in tumor cell pathogenesis, growth, angiogenesis, response to cytotoxic therapies and NO translational applications in cancer therapy, alone or in conjunction with other therapies.

The fact that tumors are composed of both tumor cells and host cells has long been known. These tumor-associated cells include vascular endothelial cells and pe- cytes, as well as inflammatory cells such as neutrophils, monocytes, macrophages, mast cells and eosinophils, and lymphocytes. The tumor cells also interact with stromal cells and with elements of the tissue extracellular matrix. What has been less appreciated is the role that these cells could have in modulating the growth, invasion, and metastasis of the tumor. Early on, the elements of what we now call the tumor microenvironment were considered to be more or less innocent bysta- ers to the role of the tumor cells as they grew and invaded local sites. Today, there is an increased understanding of the critical role of the tumor microenvironment as dramatically influencing the course of tumor development and dissemination. This volume represents a superb compilation of the latest thoughts and data regarding the role of each essential component of the tumor microenvironment in cancer development and progression. Perhaps, the earliest recognition of the role of nonmalignant cells as cancer re- lators was the recognition that lymphocytes can participate in what was termed “immune surveillance” in the 1960s. Our understanding of tumor immunity has improved markedly since then, and there are now successful clinical studies sh- ing the potential use of immune-based therapies in cancer treatment.

A practical guide to the design, conduction, analysis and reporting of clinical trials with anticancer drugs.

This book will cover primary roles of NKT cells in immunity to cancer, in both mouse tumor models and cancer patients. There are several chapters describing general aspects of NKT cells.

The book will detail the history, successes, and failures of targeted therapies for cancer, with a particular focus on IGF systems and cancer.