In the approach to the analysis of disease, including, of course, cancer, two major thrusts may be distinguished. These may be referred to, in shorthand, as agents and processes: the causative agents (chemical, microbial, physical, environmental, and psychosocial) and the organismic processes, initiated and furthered by the agents, culminating in observable pathology (at the macromolecular, cytological, histological, organ function, locomotor, and behavioral levels). The past 25 years, since the appearance of the first volume of the predecessor series (1) authored by the Editors of this present volume, have seen an impressive number of studies on chemicals (and other agents) as etiologic factors in the induction of cancer. The major emphasis has been on the discovery of many chemical carcinogens of widely different structures, their metabolism by various tissues and cells, and, in turn, their molecular-biochemical effects on the cells. This rapidly expanded body of information, as effectively covered in the predecessor volumes, is an excellent entree to the second half of the overall problem of chemical carcinogenesis, the processes. The active agents trigger a large array of molecular-biochemical alterations to which the target cells, target tissues, and target organisms respond in many select and common ways. This second major aspect of the induction of cancer by chemicals (and by other agents)- the sequence of cellular and tissue changes clearly relevant to cancer-remains the challenge for the future.

At present, there is growing interest in high pressure bioscience and biotechnology. The activities are nearly equally distributed between fundamental research and applications. With original work on marine and terrestrial microbiology, biochemicstry, molecular biology, deep-sea diving, food science and other industrial applications, this book covers the whole range of current high pressure bioscience. Advances in High Pressure Bioscience and Biotechnology will be welcomed by all industrial and academic researchers who are working in this field.

This is the first comprehensive work to review blood platelet biochemistry, physiology, pharmacology, and function. It provides up-to-date information on how platelets function, the biochemical mechanisms that modulate their physiology and function, as well as the pharmacology of platelet inhibitory drugs.

Has the neuromuscular junction been over-exposed or is it perhaps already a closed book? I asked myself this at a recent International Congress when an American colleague complained that the Journal of Physiology had articles on nothing but the neuromuscular junction, while another colleague asked why I was editing a volume on a subject about which everything was already known. It is worrying to think that these views may be shared by other people. I hope that this volume will convince my two colleagues and other readers that the neuromuscular junction is very much alive and continues to attract the interest of many workers from a variety of fields; strange as it may seem, the synapse between a motor nerve ending and muscle fibre, with its relatively simple architecture, is one of the most inter esting sites in the body-I do hope we have done it justice. The various chapters of this volume present a cross section of knowledge as viewed by a group of 13 individuals, actively engaged in research. Multi-author volumes such as this are frequently criticised on the grounds that chapters or sec tions overlap. I believe that such criticium is only valid where the overlap is repetitious. Where it results in the reader having available discussions of material from differing stand-points, overlap becomes a valuable feature of this type of publication."

Leading scientists offer detailed profiles of ten protein drugs currently in development. The case histories of these important new compounds are described from the perspective of their formulation, characterization, and stability. This ready reference also features recent data and an abundance of previously unpublished information. The in-depth coverage includes a highly useful compendium of degradation sites occurring in over 70 proteins. An invaluable aid in the rapid identification of potential 'hot spots' in proteins, this accessible compilation allows for inspection of the protein's primary structure and preparation of a hydroflex plot.

From beach encounters, aquaculture perils, and processed-food poisoning to snake bites and biological warfare, natural toxins seem never to be far from the public's sight. A better understanding of toxins in terms of their origin, structure, structure-function relation ships, mechanism of action, and detection and diagnosis is of utmost importance to human and animal food safety, nutrition, and health. In addition, it is now clear that many of the toxins can be used as scientific tools to explore the molecular mechanism of several biological processes, be it a mechanism involved in the function of membrane channels, exocytosis, or cytotoxicity. Several of the natural toxins have also been approved as therapeutic drugs, which has made them of interest to several pharmaceutical companies. For example, botulinum neurotoxins, which have been used in studies in the field of neurobiology, have also been used directly as therapeutic drugs against several neuromus cular diseases, such as strabismus and blepherospasm. Toxins in combination with modem biotechnological approaches are also being investigated for their potential use against certain deadly medical problems. For example, a combination of plant toxin ricin and antibodies is being developed for the treatment of tumors. The great potential of natural toxins has attracted scientists of varying backgrounds-pure chemists to cancer biologists-to the study of fundamental aspects of the actions of these toxins."

Arthropod venoms have received much attention and have played an important role in folklore and medicine since ancient times. Scorpion envenomation, "tarant ism," bee and wasp stings are among those subjects about which most has been speculated and written in the past. In the last 50 years or so, a great number of scientific papers have been devoted to arthropod venoms, but only a few volumes have been designed to collect this rapidly increasing material, and these are not recent. Of late, the chemistry and mode of action of several arthropod venoms have been thoroughly studied, and some of these substances will probably be used as pharmacological tools and also as therapeutic agents. The aim of the present volume is to collect in manual form new information as well as the old notions on arthropod venoms. Even though it was our intention to present a volume on arthropod venoms, and not on venomous arthropods, inevitably we were forced to include information on venom-producing organisms as well. We assumed, in fact, that those scientists for whom the present manual is primarily intended (biochemists, particularly com parative biochemists, and pharmacologists) should be familiar with the biologic elements concerning the venom-producing species; which should show them how important it is to operate in close collaboration with biologists specialized in venomous arthropod systematics and biology."

The present volume represents the proceedings of the symposium on npyridine Nucleotide-Dependent Dehydrogenases" which was held on the campus of the re cently established University of Konstanz, Germany, from September 15 to 20, 1969. The aim of the symposium was to provide a forum for discussion among the experts interested in the various aspects of pyridine nucleotide-dependent de hydrogenases and the pyridine coenzymes, so as to evaluate the state of the present knowledge and to stimulate further progress in this field. In order to facilitate discussion and personal contact it was necessary to restrict the number of participants to 90 including the invited speakers, who came from fifteen countries (Australia, Austria, Denmark, England, Finland, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Sweden, Switzerland, USA). The printed lectures in this volume differ only in minor respects from those circulated be fore the meeting. In some cases speakers presented new experimen tal material during the symposium which was added as an addendum to the papers. The discussions were not recorded. The participants were requested to provide a written report of what they considered worth including in the published re port. This, together with the answers of the speakers is presented in this vo lume. I whish to thank all the speakers and discussants for their cooperativity in preparing the manuscript. The symposium was sponsored by the International Union of Biochemistry whose President, Professor Theorell, was also present and who was acting as one of the speakers and chairmen."

This publication of a symposium held on 24 th and 25 th of June 1988 in Munich th is dedicated to Nepomuk Zollner on the occasion of his 65 birthday, expressing the best wishes of the authors. Nepomuk Zollner was born in the northern part of Bavaria. While a medical student in Munich he was called up to military duty in the last year of World War II. After achieving excellent results on his examinations he served as a physician in several hospitals in Munich and soon became interested in inborn errors of metabolism. In order to receive the best education possible at that time he joined the group of S. J. Thannhauser, the famous German emigrant, in Boston where he worked from 1951 to 1953. There he was able to continue his studies on lipids, which he had started in 1948, and begin with his studies on purine metabolism. While working in Thannhauser's laboratory he learned to think and act according to the strict laws of natural SCIence. After returning to Europe he concentrated his scientific work on purines and lipids. Gout and hyperlipoproteinemias from the genetic to the therapeutic aspects remained the dominating topics of his research activities. In spite of many obligations as head of the Medical Polyclinic of the University of Munich and many activities at the university and in scientific societies Zollner's foremost intent continued to be the development and progress of natural science in medicine.

Cell biology has made an appreciable impact on the evaluation of physiological and pathophysiological processes leading to a more detailed understanding of the signaling mechanisms by which cells communicate in vivo and in vitro and modify adaptively. By using cell culture models in addition to animal experiments we are now able to better define the overall and the selective potential of drugs. This book is designed to give information on the advantages and limitations and on new aspects and the meaning of cell culture models in pharmaceutical research.

Seventeen years after its initial description, nuclear factor-KB (NF-KB) endures as one of the most studied transcription factors. NF-KB has attracted widespread interest based on the variety of stimuli that activate it, the diverse genes and bio logical responses that it controls, the striking evolutionary conservation of struc ture and function among species, and its involvement in a variety of human diseases. The biochemical basis by which several stimuli converge to activate NF-KB has been largely elucidated during recent years. While first discovered as a key regulatory factor of the immune system, NF-KB is now recognized as an important player in the functioning of many organs and cell types. The ongoing examination of NF-KB signaling has revealed its ever expanding role in immune and inflammatory responses, but also in cancer and development. For this reason, numerous efforts are underway to develop safe inhibitors of NF-KB to be used in the treatment of both chronic and acute disease situations. The present book is the first to review and synthesize our knowledge of this interesting transcription factor. As such, the choice of subjects to review was daunting. To set the stage, an introductory chapter on activators and target genes, as well as the role they play in several responses, has been included."

The Sixth International Conference on Miniaturized Chemical and Biochemical Analysis Systems, known as IlTAS2002, will be fully dedicated to the latest scientific and technological developments in the field of miniaturized devices and systems for realizing not only chemical and biochemical analysis but also synthesis. The first IlTAS meeting was held in Enschede in 1994 with approximately 160 participants, bringing together the scientists with background in analytical and biochemistry with those with Micro Electro Mechanical Systems (MEMS) in one workshop. We are grateful to Piet Bergveld and Albert van den Berg of MESA Research Institute of the University of Twente for their great efforts to arrange this exciting first meeting. The policy of the meeting was succeeded by late Prof. Dr. Michael Widmer in the second meeting, IlTAS'96 held in Basel with 275 participants. The first two meetings were held as informal workshops. From the third workshop, IlTAS'98 (420 participants) held in Banff, the workshop had become a worldwide conference. Participants continued to increase in IlTAS2000 (about 500 participants) held in Enschede and IlTAS2001 (about 700 participants) held in Monterey. The number of submitted papers also dramatically increased in this period from 130 in 1998, 230 in 2000 to nearly 400 in 2001. From 2001, IlTAS became an annual symposium. The steering committee meeting held in Monterey, confirmed the policy of former IlTAS that quality rather than quantity would be the key-point and that the parallel-session format throughout the 3.

HMG-CoA reductase inhibitors (statins) are established drugs for the treatment of hypercholesterolemia. Furthermore, they induce regression of vascular atherosclerosis as well as reduction of cardiovascular-related morbidity and death in patients with and without coronary artery disease. This book deals with statins which have substantially altered the approach to therapy of atherosclerosis and its sequelae. Emphasis is placed on the scientific background to the discoveries and the development of the therapy, including an overview of the current state of knowledge of the drugs. Clinical data are reviewed extensively. This book not only provides the reader with valuable information but also stimulates further research into the pathogenesis of atherosclerosis and the mechanisms behind the action of effective statins. It sets the stage for creative thinking among scientists of many disciplines for the accomplishment of our ultimate goals in treating atherosclerosis and its sequelae. This topical volume...

In this volume we have included some contributions among the plenary lectures, oral presentations and posters that have been presented at the 1st Joint Greek-Italian Meeting on "The Chemistry of Biological systems and Molecular Chemical Engineering" organized at Loutraki, Club Poseidon, Greece 1990. We hope similar meetings will follow every two years alternating between the two countries in order to strengthen the scientific ties among the scientists working in this field. The inter- disciplary aspect of the meeting has been evident by the wide presence of scientists in bioinorganic, bio-organic, biological fields and molecular engineers who will get together and exchange ideas and experiences. We take this opportunity to thank the Greek Chemical Society, the Italian Chemical Society, the "Gruppo Interdivisionale di Chimica dei Sistemi e dei Processi Biologici", Consiglio Nazionale delle Ricerche, Nuclear Research Center "Demokritos" and the Greek Ministry for Research and Technology. ENRICO RIZZARELLI THEOPHILE THEOPHANIDES CONTRIBUTORS Numbers in parentheses indicate the pages on which the author's contributions begin Mojgan Aghazode Tabrizi, Department of Pharmaceutical Science, via Scandiana 21, University of Ferrara, 44100 Ferrara, ITALY (119) Maria Albano, Department of Chemistry, University of Calabria, Arcavacata di Rende, 87030 Cosenza ITALY (23) Rossano Amadelli, Photochemical Center of C. N. R. , Department of Chemistry, University of Ferrara, via L. Borsari 46, 44100 Ferrara, ITALY (103) Amalia Anagnostopoulou-Konsta, Department of Physics, National Technical University, 57 73 Athens, GREECE (45) Jane D.

One of the surprising things about the natural world is that animals are dying around us all the time and yet we rarely see any evidence of it. This is a testimony to the efficiency of the large variety of organisms which decompose animal corpses. Whilst bacteria and fungi are the main groups involved in decomposition processes, the larger insects additionally provide an important physical disruption of body tissues, which aids the penetration of micro organisms and speeds the collapse of the body structure. A human corpse is treated no differently and the same groups of organisms are involved. From a forensic science viewpoint the universality of the decay process provides two major advantages. Information based on the decomposition of animals is of considerable value when considering human cases and the successional pattern of decay is broadly equivalent wherever the process is being studied. Historically, the usefulness of insects in solving crime can be traced back in the literature to the 13th century. McKnight 1, 2] translated a Chinese text of this period which contains an account of how a law officer dealt with a case of murder in the rice fields. Death had been caused by a sickle and the official ordered all the field workers to line up and lay their sickles on the ground in front of them. Flies began to be attracted to one of the sickles whereupon its owner confessed to the crime."

Scientists from many disciplines require making observations which are dependent upon the behavior of compounds in solution. This ranges from areas in geography, such as oceanography, to areas in chemistry, such as chromatography, to areas in biology, such as pharmacology. Historically, information would be obtained by observing a response for a given set of conditions and then the conditions would be changed and a new response obtained. In this approach there would be little effort made to actually understand how a compound was behaving in solution but rather just the response was noted. Understanding the behavior of compounds in solution is critical to understanding their behavior in biological systems. This has become increasingly important during the last twenty years as an understanding of the biochemistry related to human illness has become better understood. The development of the pharmaceutical industry and the need to rapidly screen large numbers of compounds has made scientists in the area of drug development aware that the pharmacological activity of compounds can be predicted by knowing their solution physical chemical properties. This is not to say that a specific drug-active site interaction can be predicted but rather a prediction can be made whether or not a compound will be absorbed, transported, or distributed within a physiological system in such a way that an interaction can occur.

Recombinant protein drugs are intimately associated with the impressive success story of the Biotech Industry during the past thirty years, some of them belonging to the most successful pharmaceutical products. More than thirty different proteins are available for a variety of clinical applications, over 300 proteins are presently being evaluated in clinical trials. In this new volume of the MDT series, historical, technical and clinical aspects of recombinant protein drug discovery and development are presented, covering past, present and future highlights. Leading scientists and co-founders of early Biotech companies describe technical breakthroughs and the fascinating story of pioneering discoveries, as well as the long way of translating them into products and business. Therefore, this book represents an exciting documentation of the beginning of a new era in the pharmaceutical industry. In addition, scientists from basic research, clinic and industry actively involved in new developments discuss...

TheNATO AdvancedStudiesInstituteseries"TargetingofDrugs"wasoriginatedin 1981. It is nowamajorinternationalforum,heldeverytwo yearsin CapeSounion,Greece,in whichthepresentandthefutureofthisimportantareaofresearch in drugdeliveryisdiscussed in greatdepth. PreviousASIsoftheseriesdealtwith drugcarriersofnaturalandsynthetic origin,theirinteractionswith thebiologicalmilieu, waysby whichthefunctionofdrugcarriers iscircumvented and,morerecently,with avarietyofapproaches to carrierdesignor modificationthatcontributeto optimalcarrierfunction. Thepresentbookcontainsthe proceedings ofthe8thNATO ASI, "TargetingofDrugs:Strategies for Oligonucleotideand GeneDelivery in Therapy", held in CapeSounionduring24June-5 July 1995. Asthetitle implies,thebookdealswith avarietyofsystemsin termsoftheirability to transportnucleic acidsto targetareasin vitro andin vivo in waysthateffectivelymodify,supplement, correct, orcurtailthefunctionofgenesin therapy. Weexpressourappreciation to Mrs. ConchaPerringfor herassistance with the organizationoftheASI. TheASI washeldunderthesponsorship ofNATO ScientificAffairs Division andco-sponsored andgenerouslyfinancedby SmithKlineBeechamPharmaceuticals (KingofPrussia). Financialassistance wasalsoprovidedby SandozPharma(Baseland Athens),GeneMedicine (Houston,USA), ChironCorporation(Emeryville,USA), BYK GuldenLombergChemische (Konstanz,Gernlany),HelpSA(Athens,Greece),Avanti Polar Lipids Inc (Birmingham,USA), OxfordMolecular(Oxford,UK), Pfizer(Kent,UK), andAlza Corporation(PaloAlto, USA). GregoryGregoriadis BrendaMcCormack v CONTENTS Gene Therapy for Inherited Genetic Disease: Possibilities and Problems c. *Coutelle Gene Delivery and Therapy: The Case for Cystic Fibrosis 15 E. W. F. W. Alton Immune Responses with Direct Gene Transfer: DNA Vaccines and 21 Implications for Gene Therapy H. L. Davis Oligonucleotides: Molecular Versions for Optimal Use in Vivo 31 E. Saison-Behmoaras, A. Van Aerschot, I. Duroux, C. Hendrix, C. Helene, and P. Herdewijn Retrovirus Vectors in Gene Therapy: Targeting to Specific Cells 45 AJ. Kingsman, Y. Bae, J. c. Griffiths, N. Kim, E. E. Ramsdale, G. Romano, Y. Soneoka, P. M. Cannon, and S. M. Kingsman Adenovirus as Vectors for Gene Therapy 53 M. G. Lee Receptor-Mediated Gene Delivery with Synthetic Virus-like Particles 67 E. Wagner, M. Cotten, and K. Zatloukal Controllable Gene Therapy: Recent Advances in Non-Viral Gene Delivery 79 A.

Sequence-specific DNA binding ligands, amongst which triple helix forming oligonucleotides are the most efficient as yet, represent promising tools in a number of fields. One of their most promising applications is as antiviral tools: they can specifically target a viral gene, even if it is integrated into the host genome, and be used to specifically inactivate the viral gene or even destroy the cells harboring this gene. However, from science fiction to science there remains a gap; and we are at the moment on the threshold of this fascinating field. Triple Helix Forming Oligonucleotides considers the different aspects of the design and improvement, current or future, of these molecules and their structural analysis, as well as their applications, with special emphasis on the attempts to obtain biological effects of these potentially important tools. What emerges is that the current state of the research is encouraging, and that these molecules are already useful in some biotechnology applications.

Hepatic cells are involved in the metabolization and elimination of a variety of endogenous and exogenous substances. They mediate the uptake, processing and subsequent secretion of biliary compounds, such as various drugs or hormones, and the passage of metabolites to be released into different blood compartments. To perform vectorial passages hepatocytes show a strong polarity with sites for endocytotic processes or specific carrier molecules, and a specified system of organelles for intracellular transport and sorting, metabolization and secretion of compounds. Several aspects, e.g. regulation, control and mechanisms of hepatic traffic are reported in detail - complemented by methodological approaches to analyse and monitor these processes.

Protein-protein interactions are involved in muscle contraction and signal transduction. This book describes how synthetic peptides may be used, much like antibodies, both as specific inhibitors and as molecular probes to explore the cognitive interfaces between interacting proteins and their functional significance. This offers the prospect of very selective intervention in cellular mechanisms. These timely contributions by several experts will appeal to the researchers in muscle physiology, cardiovascular pharmacology and cell biology who are interested in this new approach.

The synthetic chemistry of carbohydrates has advanced at a scarcely equalled rate in the last 25 years, due to the great interest of biologically active natural products coritaining sugar moieties. It suffices to note that in the review by J. D. Dutcher appearing in "Advances in Carbohydrate Chemistry" vol. 18, 1963, only the structures of less than ten aminodeoxy sugars were reported. This book deals exclusively with a single class of carbohydrates, namely the aminodeoxy sugars of antibiotics, the most popular of which is probably daunosamine, a compound for which more than 20 different synthetic approaches have been reported in the literature since the publication of its structure in 1964. No compound in the 3-amino-2-deoxY-L-hexose series had been prepared by chemical synthesis when we started our synthetic work in this field in 1972 on the wave of the successful therapeutic applications of adriamycin. The compounds with xylo stereochemistry were unknown even in the more easily accessible D-series. The size of this book documents the rapid development of the field. I wish to add that the improvements of chemical methodology reported in. the volume outspan the specific field and are of importance in the design of synthetic approaches to other carbohydrate structures. These also include compounds involved in chemical interactions of great biological interest, but hitherto un explained at the molecular level, such as those related with cell recognition, adhesiveness and differentiation."