When Antibiotics I was published in 1967, the teleological view was held by some that" antibiotics" were substances elaborated by certain microorgan isms for the purpose of competing with other microorganisms for survival in mixed ecological environments. However, not only had J. EHRLICH and his associates shown 15 years earlier that chloramphenicol was produced by Strepto myces venezuelae in cultures of sterilized soils but not in parallel cultures of the same soils which were not sterilized, but operationally, the search for anti cancer antibiotics was actively under way (Antibiotics I reporting on numerous such substances), although the concept of antibiosis could not logically justify such undertakings. This editor hesitates to accept the use of the term "antibiotic" for anti microbial agents of non microbiological origins which is sometimes encountered, but neither does he subscribe to the view that antibiotics are in some fundamental manner different from chemotherapeutic substances of other origins. Modes and mechanisms of action of chemotherapeutic compounds are not systematic functions of their origins nor of the taxonomical position of the target organisms. Consequently, in the selection of topics for Antibiotics III (published in 1975), synthetic drugs and natural products of higher plants (alkaloids) were represented, along with antibiotics in the strict sense of the definition. We now present Antibiotics V, for whose assembly the same selection criteria were applied as for Antibiotics Ill. The aggregate length of the contributions rendered it impractical to place the entire text between the covers of one book.

The first volume of Antibiotics was published in 1967 and contained a series of review papers on antibiotic actions. The editors, Drs. GOTTLIEB and SHAW, were aware of the rapid development of this field of study and provided a number of addenda in an effort to keep knowledge up to date while the book was in production. One year after the publication of Antibiotics I, this editor had a conference with Dr. KONRAD F. SPRINGER in which it became clear that another volume on actions of antibiotics would be necessary. For a variety of reasons, this was delayed until 1975 and became Antibiotics III. It did not contain addenda since it was recognized by the editors, Drs. CORCORAN and HAHN, that still another volume would have to follow and that in a moving field, such as the study of the actions of antibacterial drugs, no publication can be definitive or remain current, except for a limited period of time. The editors of Volume III grouped the contributions into sections: 1. Inter ference with nucleic acid biosyntheses, 2. Interference with protein biosynthesis, and 3. Interference with cell wall/membrane biosynthesis, specific enzyme sys tems, and those in which the mode of action was not known with certainty.

The rapid advances made in the study of the synthesis, structure and function of biological macromolecules in the last fifteen years have enabled scientists concerned with antimicrobial agents to achieve a considerable measure of understanding of how these substances inhibit cell growth and division. The use of antimicrobial agents as highly specific inhibitors has in turn substantially assisted the investigation of complex biochemical pro cesses. The literature in Ihis field is so extensive however, that we considered an attempt should be made to draw together in an introductory book the more significant studies of recent years. This book, which is in fact based on lec ture courses given by us to undergraduates at Liverpool and Manchester Universities, is therefore intended as an introduction 'to the biochemistry of antimicrobial action for advanced students in many disciplines. We hope that it may also be useful to established scientists who are new to this area of research. The book is concerned with a discussion of medically important antimicro bial compounds and also a number of agents that, although having no medical uses, have proved invaluable as research tools in biochemistry. Our aim has been to esent pr the available information in a simple and readable way, emphasizing the established facts rather than more controversial material. Whenever possible, however, we have indicated the gaps in the present knowledge of the subject where further information is required.

" . . . the motto for the therapeutics of the future will have to be de sedibus et causis pharmacorum. " P. EHRLICH, 1909 Exciting events in the basic disciplines of virology, immunology, and pharmacology continue to advance the understanding of the pathogenesis and control of virus diseases. At the same time, the rational development of antiviral agents is attracting, to an increasing extent, the interest of workers in other disciplines. Improvements in technology facilitate the definition of potential target sites for antiviral intervention and unmask new viral and host genes. The outcome is a further steady development of new antiviral agents which approach the "magic bullets" first proposed by PAUL EHRLICH. Remarkable advances in protein synthetic methods that yield polypeptides which inhibit active sites of viral proteins have aided substantially in the basic and clinical study of these antiviral agents. In addition, the extremely rapid progression in recombinant DNA techniques, leading to the synthesis of large quantities of gene products, is also increasing our opportunities at a dashing pace. New information and developing technology facilitate research on the mechanism of action, toxicity, pharmacokinetics, and pharmacodynamics of new agents. The list of clinically effective antiviral agents is expanding and the number of potentially useful compounds is growing rapidly. This book is a combined theoretical text and practical manual which, it is hoped, will be of use to all who have an interest in virus diseases, particularly scientists, physicians and graduate students.

It is not certain that the editors of Antibiotics I (1967), Drs. GOTTLffiB and SHAW, fully realized that they were laying the foundation for an entire series of which we present here Vol. VI. For some time to come, this will be the last volume of the Antibiotics series. There are several reasons for this. Firstly, the discovery of medicinally useful antibiotics has leveled off, because the number of microbiological products with antimicrobial properties is not infinite. In 1972 some 2500 antibiotic substances were known, of which approximately one per cent are clinically useful. Further search for antibiotics has led to increasing frequency of rediscoveries and drasti cally decreasing frequency of discoveries of new antibiotics. As the search for antibiotics with a standard methodology in conventional ecological niches has exhausted itself, there is a paucity of new and interesting substances on which to undertake modes/mechanisms of action studies. Secondly, the mechanism of action field has come of age and its results are now academic knowledge. This also holds true for synthetic chemothera peutic drugs and becomes the case rapidly for toxic substances with anti-eukar yotic action. The study of mechanisms of action was undertaken for two reasons: one was the basic scientific desire to know how antimicrobial substances inter fered with microbial biochemistry; the second one was the hope that such infor mation would be useful in the premeditated design of synthetic antimicrobials.

The Series on Antibiotics produced by Springer-Verlag began more than a decade ago with the nearly simultaneous appearance of two volumes, one dealing with the mode of action of antibiotics and the other concerning the biosynthesis of them. The standards set by the original Editors were high, and these books have proved useful to many. The rapid advances in our knowl edge of the mode of action of antibiotics and other antitumor agents has stimu lated two further works in the same series (Volume III, 1975; and Volumes Vj1 and Vj2, 1979). For some time it had appeared to Dr. Konrad Springer that the time might' be ripe' for bringing the subject of the biosynthesis of antibiotics up-to-date. This Editor agreed to survey the literature and discuss this possibility with his colleagues who are active in research on antibiotics. In spite of the appearance of numerous review articles, both of a highly special ized and general nature, on the biosynthesis of antibiotics, it was agreed generally that it would be extremely useful to add a new volume on biosynthesis to the Series. Such a work should focus on collecting a group of contributions dealing with those antibiotics whose biosynthesis is understood in much greater detail now than it was in the middle 1960's. Since Volume II on biosynthesis continues to be available, this addition to the series has not dealt with each and every antibiotic whose biosynthesis was studied long ago.

The addition of chemotherapy as an effective means to treat cancer has had a major impact on selected human malignancies. Due to a general inability to dif ferentiate between normal and neoplastic cells, little selectivity exists in currently used oncolytic drugs. Consequently, significant toxicity to the patient is expected when systemic cancer chemotherapy is chosen as an appropriate therapeutic in tervention. Much of this toxicity, such as damage to the bone marrow, gastroin testinal tract, or hair follicles, is predictable based upon the fact that anticancer drugs kill actively dividing cells. These types of toxicities, while serious, are usually manageable and reversible and are, therefore, not often considered to be dose limiting. Unfortunately, several of the most important anticancer drugs also damage tissues in which the growth fraction is relatively small. Such toxicities can not be predicted based on the chemical structure of the drugs, are often not detected in preclinical studies, and are encountered frequently for the first time in clinical studies. Further, unlike most of the proliferative-dependent toxicities, the unpre dicted toxicities are usually irreversible or only partially reversible upon cessation of drug administration. Because of this, the unpredicted toxicities are referred to as dose limiting. They represent a significant barrier to the ultimate efficacy of several of our most important anticancer drugs.