Mechanisms of Chemical Carcinogenesis provides information pertinent to the fundamental mechanisms of chemical carcinogenesis. This book surveys the interactions of chemical carcinogens with native DNA, the activation of normal cellular sequences, and the transforming role of the activated genes. Organized into seven chapters, this book begins with an overview of the relationship between the incidence of lung cancer and the frequency and duration of cigarette smoking. This text then examines the concept that carcinogens may require metabolic activation before they initiate carcinogenesis. Other chapters consider the structure of the nucleoside adducts resulting from the hydrolysis of salmon-sperm DNA and rat-liver ribosomal RNA. This book discusses as well the persistence of nucleoside analogues in target-tissue nucleic acid. The final chapter deals with mutational theory. This book is a valuable resource for workers involved with cancer research, toxicology, and molecular biology. Specialists in drug development, industrial hygiene and occupational medicine will also find this book useful.

This book is one of a GANN Monograph on Cancer Research series and is based on a Japanese Cancer Association-sponsored symposium entitled "Multiplicity of Chemical Carcinogen-Activating Enzymes· with Particular Emphasis on Cytochrome P-450" which was held in Tokyo on November 21, 1983. The principal role of microsomal cytochrome P-450 in the metabolic activation of various chemical carcinogens in animal cells has been well established. The activated chemical carcinogens induce mutations of the cells, which is an essential part of the initiation of chemical carcinogenesis. Since microsomal cytochrome P-450 in various animal tissues includes multiple molecular species with different substrate specificities and different responses to chemical inducers, knowledge of the molecular and catalytic properties and the inducibilities of those cytochrome P-450 forms is surely a most important base from which to elucidate the mechanism of chemical carcinogenesis. The focus of the symposium was this area of molecular diversity and inducibility of microsomal cytochrome P-450 in animal tissues. The mechanism of activation of various types of chemical carcinogens by cytochrome P-450 and related enzymes was another main topic. The editors, who were also the symposium organizers, hope these summaries of current research in this field in Japan will stimulate future development of studies on the mechanism of chemical carcinogenesis.

This volume will provide a contemporary account of advances in chemical carcinogenesis. It will promote the view that it is chemical alteration of the DNA that is a route cause of many cancers. The multi-stage model of chemical carcinogenesis, exposure to major classes of human carcinogens and their mode-of-action will be a focal point. The balance between metabolic activation to form biological reactive intermediates and their detoxification, ensuing DNA-lesions and their repair will be profiled. It will describe the chemical changes that occur in DNA that result from endogenous insults including epigenetic changes that lead to gene silencing. It will describe major mechanisms of mutagenesis, affects on tumor suppressor genes and proto-oncogenes, and how cell-cycle check points can be by-passed by the "stealth-like" properties of chemical carcinogens. Environmental agents that can promote tumor formation will be discussed. The monograph will have wide appeal as a knowledge base for graduate students, post-doctoral fellows and faculty interested in this aspect of cancer causation and research.

I have been privileged to witness and participate in the great growth of knowledge on chemical carcinogenesis and mutagenesis since 1939 when I entered graduate school in biochemistry at the University of Wisconsin Madison. I immediately started to work with the carcinogenic aminoazo dyes un der the direction of Professor CARL BAUMANN. In 1942 I joined a fellow graduate student, ELIZABE1H CAVERT, in marriage and we soon commenced a joyous part nership in research on chemical carcinogenesis at the McArdle Laboratory for Cancer Research in the University of Wisconsin Medical School in Madison. This collaboration lasted 45 years. I am very grateful that this volume is dedi cated to the memory of Elizabeth. The important and varied topics that are reviewed here attest to the continued growth of the fields of chemical car cinogenesis and mutagenesis, including their recent and fruitful union with viral oncology. I feel very optimistic about the application of knowledge in these fields to the eventual solution of numerous problems, including the detection and estimation of the risks to humans of environmental chemical carcinogens and re lated factors.

About two centuries after the communication by Sir Percival Pott that the "chimney sweeper disease" was a cancer and its suggestion that active compounds of soot were the causative agents, and about one century after the description of urinary bladder cancer in dye workers, an enormous number of substances have been synthesized and have probably come into contact with man. Research in cancer prevention is of primary importance, and may receive continuous support from new discoveries on cancer etiology and pathogenesis. If one accepts the multistage model of chemical carcinogenesis, one has also to accept that many events occur between the contact of carcino genic compounds and their specific targets and the development of a clinically recognizable neoplasm. Thus, animal studies become essential to elucidate the different steps by which chemical carcinogens induce neoplasia. The analysis of these steps and the comparative evaluation of experimental models is essential to an understanding of pathogenesis.

During half a century, cytochrome P450 in its original uniqueness as an optically "wrong" cytochrome has attracted many investigators, who have contributed to the unveiling of a bewildering multiplicity of biologically important functions of the, by now very large, superfamily of cytochrome P 450 enzymes. With its discovery in 1958 and with the advent of more refined spectroscopic methodologies, through the double wavelength spectrophotometry, the mysterious enzyme system began to reveal its secrets in a swift stream of investigative successes. As one of the most extensively studied enzyme systems worldwide the interest in cytochromes P450 very much reflects its importance in the elimination of drugs and other chemicals from the body and its role in chemical toxicity and in the aetiology of diseases such as cancer. There has been significant progress in research in this area in recent years and current books on this subject are now out of date. This much needed, new, fully up-to-date publication fills this gap and emphasises the new relevant topics that have emerged during the last decade in an easily accessible manner. The enzyme system, cytochromes P450, comprises a number of families/subfamilies, and the focus of the book is to deal with each individually, furnishing information directly relevant to scientists involved in the development of chemicals, in particular in the evaluation of their safety. The book has contributions from internationally respected scientists who are research-active in the relevant areas. The authors have made extensive use of figures and tables so that the reader can access the necessary information without always having to read the text. In addition, a very extensive, user-friendly index is a unique hallmark of the book. Part A of this monograph introduces the reader to the current knowledge of the evolutionary development of cytochrome P450 structure and function. Furthermore, it deals with the role of this enzyme in the formation of reactive intermediates. The shrewd and extensive utilisation of the molecular biology methodology very rapidly led to a vast body of enzymes calling for a classification of the plethora of different cytochromes P450 (the superfamily) into families and subfamilies. This is aptly exemplified by the ten chapters in Part B of this book, dealing with ten subfamilies and two families of cytochrome P450. Part C offers an insight into another aspect of cytochrome P450 research, namely its regulation through receptor-mediated stimuli - as opposed to enzyme induction or inhibition. The final chapter translates the current data on one of several drug metabolising systems into clinical application and highlights the role of cytochromes P450 in the treatment of neoplastic growth. The book deals extensively with each family/subfamily of the cytochromes P450 that contribute to the metabolism of xenobiotics. Essential and invaluable information is provided for the industrial research scientist working with fine chemicals, and especially those in the pharmaceutical industry, dealing with the safety evaluation of chemicals or being involved in the study of their metabolism, pharmacokinetics and toxicological properties. It should also prove of interest to Regulators concerned with the safety evaluation of chemicals, research pharmacologists and toxicologists, and postgraduate students studying drug metabolism and toxicology at an advanced level.