This book is an up-to-date review of current knowledge in the field of multiple drug resistance in human cancer. The literature up to the middle of 1993 is surveyed in specialist chapters written by different experts. Topics covered include the molecular genetics, cytogenetics and biochemistry of the mdr genes and P-glycoprotein; alternative transport proteins in MDR; topoisomerases I and II; cytochrome p450-enzymes and glutathione- S-transferases in MDR; cellular models for MDR in solid tumours and haemopoietic tumours; immunochemical and molecular biological techniques for detection of MDR-related gene expression; and clinical and pharmacological strategies to circumvent resistance. The book brings together a new combination of approaches to this serious clinical problem.

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.

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.

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.

More than 40 years ago, the observation that doxorubicin-resistant tumor cells were cross-resistant to several structurally different anticancer agents was the first step in the discovery of P-glycoprotein (P-gp). P-gp belongs to the superfamily of ATP-binding cassette (ABC) transporters;its overexpression has become a therapeutic target for overcoming multidrug resistance in tumors. However, P-gp is also expressed in cells of normal tissues where it plays a physiological role, by protecting them from the toxic effects of xenobiotics. Also, ABCB1 gene polymorphisms may influence the response to anticancer drugs substrate of P-gp. Several strategies to overcome P-gp tumor drug resistance have been suggested. P-gp 'circumvention’ is the most explored and is based on the coadministration of anticancer agents and pump inhibitors (P-gp modulators). Despite the positive findings obtained in preclinical studies, results of clinical trials are not yet successful and clinical research is still ongoing. Other investigational approaches have been studied (e.g. P-gp targeting antibodies, use of antisense strategies or transcriptional regulators targeting ABCB1 gene expression) but their use is still circumscribed to the preclinical setting. A further approach is represented by the encapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles. This strategy has shown higher efficacy in tumor previously treated with the free drug. The reasons explaining the increased efficacy of liposomal/nanoparticle-based drugs in Pgp-overexpressing tumors include the coating with specific surfactants, the composition changes in the plasma membrane microdomains where P-gp is embedded, the direct impairment of P-gp catalytic mechanisms exerted by specific component of the liposomal shell, but are not yet fully understood. A second strategy to overcome P-gp tumor drug resistance is represented by exploiting the P-gp presence. Actually, P-gp-overexpressing cells show increased sensitivity (collateral sensitivity) to some drugs (e.g. verapamil, narcotic analgesics) and to some investigational compounds (e.g. NSC73306). P-gp-overexpressing cell are hypersensitive to reactive oxygen species, to agents perturbing the energetic metabolic pathways, changing the membrane compositions, reducing the efflux of endogenous toxic catabolites. However, the mechanisms explaining collateral sensitivity have not been fully elucidated. Another approach to exploit P-gp is represented by ABCB1 gene transfer to transform bone marrow progenitor cells into a drug resistant state which may allow conventional or higher doses of anticancer drug substrates of P-gp to be administered safely after transplantation. More recently the development and introduction in the clinics of anticancer drugs which are not substrates of P-gp (e.g. new microtubule modulators, topoisomerase inhibitors) has provided a new and promising strategy to overcome P-gp tumor drug resistance (P-gp 'evasion'). This ‘research topic’ issue aims at exploding the above mentioned matters, in particular by: -retracing the history of the first researches on P-gp - describing the physiological role of P-gp - describing the molecular basis, structural features and mechanism of action of P-gp - describing diagnostic laboratory methods useful to determine the expression of P-gp and its transporter function - describing strategies to overcome tumor drug resistance due to P-gp and other ABC transporters - indicating novel approaches to overcome P-gp multidrug resistance, ranging from basic research studies to pre-clinical/clinical studies.

The recent appearance of multi-drug resistant phenotypes has complicated the efforts to completely eradicate diseases such as tuberculosis and malaria, thus underscoring the need for new and innovative scientific approach to the problem. Multi-Drug Resistance in Emerging and Re-Emerging Diseases highlights the state-of-the-art in microbial/parasite control and containment, and discusses ways and means of avoiding development of drug resistance. It explores strategies to combat the nightmare of microbial aggression and resistance and to overcome multiple drug resistance when it emerges in microbial organisms or in cancer cells exposed to chemotherapy. Written by a panel of experts, the book gives you the benefits of both field and clinical experience as well as an in-depth know-how of the pathology of these drug resistant diseases. Topics include malaria, tuberculosis, cholera, leprosy, diarrhoeal diseases, nosocomial diseases, plague, and drug resistance and cancer. Multi-Drug Resistance in Emerging and Re-Emerging Diseases provides a foundation for new initiatives and more collaborative efforts in the fight against resistance to antibiotics by micro-organisms.