This critical, state-of-the-art review brings together the scattered and often controversial information on multidrug resistance reversal. Leading scientists in the field cover P-glycoprotein, the genetics of resistance, and its reversal by drugs. Resistance modifiers and modulators are tabulated and critically evaluated. Reversal of Multidrug Resistance in Cancer is important reading for oncologists, cancer chemotherapists, and other cancer researchers.

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 . . . . . . . . . . . . . . . . . . . . . . . . . .

Nullius in verba. . . Truth will be tested not by words. Horace (Epistles) Few read introductions except for book reviewers, who want to take a shortcut and avoid reading the book itself. However, tradition requires that the preface make public why the book was written at all (this is not supposed to include powerful reasons such as augmenting the ego of the editor and authors). Frequently, the inflationary tendency to publish in verbose length is in conflict with market forces and interest. No doubt, multidrug resistance is a "fashionable" topic, but there are many fashions displayed on the cat-walk of scientific literature. One can rationalize that the forces driving our concern with multi drug resistance reflect the frustration of pharmaceutical companies and oncologists alike: as soon as a new anticancer drug enters clinical trials, cancer cells start eluding extinction with their elaborate and successful mechanisms. Many grants have been awarded and spent, only to confirm the futility of our efforts to defeat this cellular Darwinism. Our medical and scientific training makes it hard, if not impossible, to accept that the survival of a malignant cell, alone or as part of a tissue, is part of the continuance of life. Since exposure to noxious and lethal substances is unavoidable, cells have been forced to develop a multitude of mechanisms to prevent entry or accelerate exit of such materials from intracellular space.

Drug Efflux Pumps in Cancer Resistance Pathways: From Molecular Recognition and Characterization to Possible Inhibition Strategies in Chemotherapy, Volume Seven, describes the fundamental aspects of efflux pumps of the ATP-binding cassette superfamily in cancer resistance pathways, along with strategies to target and improve chemotherapy efficacy. Pumps of the ATP-binding cassette superfamily (ABCs) regulate the access of drugs to the intracellular space. In this context, the overexpression of ABCs is a well-known mechanism of multidrug resistance in cancer and is associated with therapeutic failure. Cancer types discussed include breast, endocrine, hematologic, gastrointestinal, musculoskeletal, lung, skin and central nervous system cancers. The book is a valuable source for researchers and advanced students in cancer, biology, pharmacology, pharmaceutical sciences, biomaterials and medical/clinical sciences that are interested in accessing a comprehensive compendium on efflux pumps in mechanisms of cancer resistance. Offers comprehensive and detailed descriptions of the basic aspects of efflux pumps in a very schematic and didactic manner Describes the involvement of efflux pumps in cancer resistance in different cancer types Encompasses an updated overview on state-of-the-art approaches that capitalize on their inhibition to improve chemotherapy and overcome resistance

Amazing anticancer therapy advancements have been made in the last decade due to tremendous innovations. Nonetheless, drug resistance remains a major challenge that limits the effectiveness of anticancer therapies, causing cancer recurrence and metastasis and being a major cause of cancer-related death. Drug resistance can be caused by complex molecular mechanisms such as gene mutations, epigenetic dysregulation, microenvironment alterations, etc. Many clinical strategies, including combination therapies and epigenetic drugs, have been used to avoid or reverse drug resistance effectively. However, the progression of cancers (in patients under treatment) or the lack of response of cancer patients indicate that current approaches to overcome resistance are far from sufficient, and more work is needed.

MULTI-DRUG RESISTANCE IN CANCER The book details the mechanisms underlying multi-drug cellular resistance and the targets of novel chemotherapeutic agents. Cancer is a major killer all over the world. Even with all the progress made, chemotherapy is still the mainstay of modern cancer treatment. The progression of the cellular defeat of numerous independent anticancer drugs in terms of their chemical structure is a major barrier to successful chemotherapy. Multi-drug resistance (MDR) is a term for the fact that most cancer patients exhibit this phenomenon. According to the numbers, drug resistance carries the blame for 90% of cancer patient deaths. Refractory cancer and tumor recurrence are common outcomes of prolonged chemotherapy. Because of the prevalence of drug-resistance mutations, the difficulty of treating tumors increases and the therapeutic efficacy of drugs decreases. Multi-Drug Resistance in Cancer: Mechanism and Treatment Strategies contains nine chapters that cover topics such as: studying the mechanics of resistance to drugs by autophagy; studies to delineate the role of efflux transporters; expression of drug transporters; resistance to targeted therapies in breast cancer; advances in metallodrug driven combination treatment for cancer; and use of natural agents for the overcoming of cancer drug resistance. The book aims to provide the latest data on the mechanisms of cellular resistance to anticancer agents currently used in clinical treatment. It provides a better understanding of the mechanisms of MDR and targets of novel chemotherapy agents which should guide future research concerning new effective strategies in cancer treatment. Audience This book is written for pharmaceutical and biomedical scientists and researchers at both the bench and in the clinic who are interested in the mechanisms and strategies for overcoming cancer’s multi-drug resistance.

In chemotherapy, cancer cells may show resistance to a wide range of anticancer drugs, a phenomenon called multidrug resistance (MDR). A well-established cause of MDR in cancer cells involves transporter proteins, such as permeability-glycoprotein (P-gp), multidrug resistance associated protein-1 (MRP1) and breast cancer resistance protein (BCRP). These proteins usually cause efflux of anticancer drugs such as daunorubicin (DNR) and paclitaxel (PTX) from cells, leading to a reduction in cellular drug accumulation. Blocking the activity of transporter proteins using MDR inhibitors is an important approach to overcome drug efflux, a method called MDR reversal. The overall goal of this research was to develop microfluidic chips and methods to enhance intracellular drug accumulation in MDR cells or reverse MDR. To investigate MDR inhibition, a microfluidic method called same-single-cell analysis was used to trap and measure single cells. In this method, drug accumulation was first measured in the trapped cell treated with anticancer drug only (control experiment). Then, enhancement of drug accumulation was measured in the same single cell treated with the drug in the presence of a MDR inhibitor. Cancer cells are usually heterogeneous. This single-cell method allowed us to conduct same cell analysis that overcame the issue of cell heterogeneity. Our method also successfully demonstrated the enhancement of drug accumulation measured in the single cells from cryopreserved patient cells. In addition, the real-time measurement in single cells provided time-dependent kinetic information that correlated with the fold-increase of drug accumulation enhancement by MDR inhibitors. Most importantly, a new integrated microfluidic chip was developed to select and measure rare cancer cells among many blood cells as a model of circulating tumor cells (CTCs). Our label-free microchip was used to separate single prostate cancer cells and measure the drug accumulation enhancement by using MDR inhibitors. A method of capturing a prostate cancer cell among blood cells was developed with an ultimate goal to find the appropriate MDR inhibitors to enhance cellular accumulation of anticancer drugs, leading to more effective chemotherapy.

It is increasingly recognized that various transporter proteins are expressed throughout the body and determine absorption, tissue distribution, biliary and renal elimination of endogenous compounds and drugs and drug effects. This book will give an overview on the transporter families which are most important for drug therapy. Most chapters will focus on one transporter family highlighting tissue expression, substrates, inhibitors, knock-out mouse models and clinical studies.