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Over the last several decades, the introduction of new chemotherapeutic drugs and drug combinations has resulted in increased long term remission rates in several important tumor types. These include childhood leukemia, adult leukemias and lymphomas, as well as testicular and trophoblastic tumors. The addition of high-dose chemotherapy with growth factor and hemopoietic stem cell support has increased clinical remission rates even further. For the majority of patients with some of the more common malignancies, however, palliation (rather than cure) is still the most realistic goal of chemotherapy for metastatic disease. The failure of chemotherapy to cure metastatic cancer is commonly referred to among clinicians as "drug resistance". This phenomenon can, however, often be viewed as the survival of malignant cells that resulted from a failure to deliver an effective drug dose to the (cellular) target because of anyone of or combination of a multitude of individual factors. Clinically, this treatment failure is often viewed as the rapid occurrence of resistance at the single cell level. However, in experimental systems, stable drug resistance is usually relatively slow to emerge.
Chemotherapy is one of the major treatment options for cancer patients; however, the efficacy of chemotherapeutic management of cancer is severely limited by multidrug resistance, in that cancer cells become simultaneously resistant to many structurally and mechanistically unrelated drugs. In the past three decades, a number of mechanisms by which cancer cells acquire multidrug resistance have been discovered. In addition, the development of agents or strategies to overcome resistance has been the subject of intense study. This book contains comprehensive and up-to-date reviews of multidrug resistance mechanisms, from over-expression of ATP-binding cassette drug transporters such as P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance p- tein to the drug ratio-dependent antagonism and the paradigm of cancer stem cells. The book also includes strategies to overcome multidrug resistance, from the development of compounds that inhibit drug transporter function to the modulation of transporter expression. In addition, this book contains techniques for the detection and imaging of drug transporters, methods for the investigation of drug resistance in animal models, and strategies to evaluate the efficacy of resistance reversal agents. The book intends to provide a state-of-the-art collection of reviews and methods for both basic and clinician investigators who are interested in cancer multidrug resistance mechanisms and reversal strategies. Tianjin, China Jun Zhou v Contents Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 1 Multidrug Resistance in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bruce C. Baguley 2 Multidrug Resistance in Oncology and Beyond: From Imaging of Drug Efflux Pumps to Cellular Drug Targets . . . . . . . . . . . . . . . . . . . . . . . . . .
The importance of drug resistance in cancer chemotherapy cannot be over stated. The 500,000 patients who die every year from cancer in the United States have, in most cases, been treated with chemotherapy. Many of these patients responded initially to chemotherapy, but death resulted from the development of drug-resistant tumors. In the first volume in the series. Drug Resistance in Chemotherapy the results of comprehensive laboratory studies aimed at understanding the mechanisms for resistance to individual agents and to the development of broad cross-resistance were described. In the past 2 years there has been substantial progress in understanding the molecular biology associated with these mechanisms of drug resistance. For the first time we are starting to understand which mechanisms are playing an im portant role in human tumors, and even more importantly, clinical trials have recently been initiated in an effort to reverse specific forms of drug resistance. The purpose of this volume is to describe the new advances, both at the molecular level and in the clinic regarding mechanisms of drug resistance and potential ways this resistance can be circumvented. This volume is focused upon mechanisms of resistance associated with two major classes of anticancer drugs: alkylating agents (including cisplatin) and the natural products (e. g. , adriamycin and vinblastine). The first section of the book describes new insights into the genetic mechanisms associated with drug resistance.
Resistance to chemotherapy, and especially multi-drug resistance, represents a significant barrier to the successful treatment of cancer. This multi-author volume brings together a wide range of up-to-date reviews on different aspects of our knowledge of drug-resistance mechanisms, written by experts in the different areas. Particular attention is paid to recently discovered mechanisms relating to oncogene expression and in particular to proteins involved in regulation and execution of apoptosis. Other important topics covered include DNA repair, topoisomerases, cell cycle control, oxygenation and vascularisation of tumours, LRP, intermediate filament proteins and low-level resistance. Recent developments in understanding the role of efflux pumps (P-170, MRP) in multi-drug resistance are also reviewed. This book will be useful to clinicians and scientists working in the areas of chemotherapy, drug resistance, DNA repair and apoptosis research.
There is now a range of cytotoxic drugs that have considerable clinical usefulness in producing responses in tumors and even, in a small proportion of cases, cure. However, the acquisition of drug resistance is a major clinical problem and is perhaps the main limiting factor in successful treatment of cancer. Thus, a tumor initially sensitive to chemotherapy will, in the majority of cases, eventually recur as a resistant tumor, which will then progress. Much of our understanding of drug resistance mechanisms comes from the study of tumor cell lines grown in tissue culture. We now understand many of the - lecular mechanisms that can lead to a cell acquiring resistance to antic- cer drugs; however, we still do not know which mechanism(s) are those most relevant to the problem of clinical drug resistance. Indeed, given that many of the cytotoxic anticancer drugs were discovered by random screening, it is - clear what features give a clinically useful anticancer drug a sufficient the- peutic index to be of value. The aim of Cytotoxic Drug Resistance Mechanisms is to provide pro- cols that are appropriate for examining the mechanisms of cellular resistance to anticancer cytotoxics in human tumor samples. Tumor cell lines have been enormously useful as experimental models of drug resistance mechanisms, however they have limitations and we need to address the relevance of such mechanisms in patients’ tumors. Examining drug resistance in tumors is much more problematic than in cell lines.
Experimental chemotherapy continues to be at the forefront of cancer thera peutics. Topics covered in the preceding volume on cancer chemotherapy in this series such as study of drugs by alkaline elution, the development of the antimetabolite tiazofurin, and the treatment of germ cell tumors have become informative references to current experimentalists and practitioners. In even earlier volumes, reviews of the platinum compounds, anthracyclines, and osteosarcoma represent topics associated with such rapid progress requiring a look back to provide the appropriate perspective. Similarly, we venture to predict that the topics in this volume will become useful landmarks for future drug development and disease strategies. In the area of drug development, what is being learned about old, estab lished antineoplastics is raising renewed expectations that it will be translated into improved applications and patient benefit. For example, we now have the ability to modulate the action of alkylating agents and fluorinated pyri midines to achieve greater sensitivity. A new compound for an old target, trimetrexate, an antifolate that does not polyglutaminate, will have a role not only in treatment of neoplastic diseases, but also protozoal infection.
The development of drug-resistant cancers is considered to be the most significant obstacle to the cure of cancer today. Nearly half of all patients with cancer suffer from tumors that are intrinsically resistant to chemotherapy, and most of the remaining half develop drug resistance during the course of their treatment. This book reviews the mechanisms and clinical implications of drug resistance in cancer with unrivaled authority. The authors, who are among the leading clinicians and investigators in the field, cover topics of current clinical concern, including multiple drug resistance and its reversal, topoisomerase drugs, apoptosis, dose intensity and escalation, gene therapy and hematopoietic support.
Resistance to therapies, both targeted and systemic, and metastases to distant organs are the underlying causes of breast cancer-associated mortality. The second edition of Breast Cancer Metastasis and Drug Resistance brings together some of the leading experts to comprehensively understand breast cancer: the factors that make it lethal, and current research and clinical progress. This volume covers the following core topics: basic understanding of breast cancer (statistics, epidemiology, racial disparity and heterogeneity), metastasis and drug resistance (bone metastasis, trastuzumab resistance, tamoxifen resistance and novel therapeutic targets, including non-coding RNAs, inflammatory cytokines, cancer stem cells, ubiquitin ligases, tumor microenvironment and signaling pathways such as TRAIL, JAK-STAT and mTOR) and recent developments in the field (epigenetic regulation, microRNAs-mediated regulation, novel therapies and the clinically relevant 3D models). Experts also discuss the advances in laboratory research along with their translational and clinical implications with an overarching goal to improve the diagnosis and prognosis, particularly that of breast cancer patients with advanced disease.
Holland-Frei Cancer Medicine, Ninth Edition, offers a balanced view of the most current knowledge of cancer science and clinical oncology practice. This all-new edition is the consummate reference source for medical oncologists, radiation oncologists, internists, surgical oncologists, and others who treat cancer patients. A translational perspective throughout, integrating cancer biology with cancer management providing an in depth understanding of the disease An emphasis on multidisciplinary, research-driven patient care to improve outcomes and optimal use of all appropriate therapies Cutting-edge coverage of personalized cancer care, including molecular diagnostics and therapeutics Concise, readable, clinically relevant text with algorithms, guidelines and insight into the use of both conventional and novel drugs Includes free access to the Wiley Digital Edition providing search across the book, the full reference list with web links, illustrations and photographs, and post-publication updates
Drug Resistance in Colorectal Cancer: Molecular Mechanisms and Therapeutic Strategies, Volume Eight, summarizes the molecular mechanisms of drug resistance in colorectal cancer, along with the most up-to-date therapeutic strategies available. The book discusses reasons why colorectal tumors become refractory during the progression of the disease, but also explains how drug resistance occurs during chemotherapy. In addition, users will find the current therapeutic strategies used by clinicians in their practice in treating colorectal cancer. The combination of conventional anticancer drugs with chemotherapy-sensitizing agents plays a pivotal role in improving the outcome of colorectal cancer patients, in particular those with drug-resistant cancer cells. From a clinical point-of-view, the content of this book provides clinicians with updated therapeutic strategies for a better choice of drugs for drug-resistant colorectal cancer patients. It will be a valuable source for cancer researchers, oncologists and several members of biomedical field who are dedicated to better treat patients with colorectal cancer. Presents a systemic summary of molecular mechanisms for a quick and in-depth understanding Updates current trends in the field with pioneering information on drug resistance Encompasses both basic and clinical approaches for a better understanding of unsolved problems from a holistic point-of-view