This series of books attempts to present, in a comprehensive manner, the field of oncology divided into three major areas; etiology, biology, and therapy. These books should serve as landmarks in the rapidly expanding experimental and clinical "universe" of this field. To some, they will be introductory; to others, a summary; for all, critical comments on the futuI'e of research. In l'ecognition of the difficulties inherent in attempting to pause and reflect while experimental data emerge with ever-increasing rapidity, the presentations take the form of overviews rather than reviews. Where possible, an historical perspective on observations and experimentation which led to our present understanding is presented, the state of the art in technique and approach is reviewed, and the gaps in knowledge and in technique are indicated. The aim throughout is integration-using the findings from one approach for comparison with others. The tremendous expansion of interest in oncology as a medical-biological discipline stimulated the publication of these volumes. This expansion, well warranted in terms of the impact of oncology on human morbidity, has been characterized by at least three phenomena. First, there has been an enormous increase in money and manpower devoted to the investigation and treatment of malignancy. That the research has become more and more "directed" or program-oriented signals the interest of those beyond the scientific community in the management of the eHort. Second, increasing numbers of students are entering the field of oncology as their major training program.

Six years ago when the first edition of this volume appeared as the first of the series, questions were posed in its preface that are as valid today as they were then. In that preface, I proposed the following challenges: (1) We must identify carcinogenic agents, and by an analysis of their "nature," e. g. , structure and physical characteristics, we may better understand their mechanism of action. (2) We must identify crucial interactions between these carcinogens and impor­ tant macromolecules within the cell, distinguishing those which relate to carcinogenesis from those which are extraneous. (3) We must examine the alterations of cell function induced by these reactions, for it is with an understanding of phenotypic variation that we may know why malignant cells escape from normal homeostatic control. (4) Last, and perhaps of greatest importance, we must define malignancy--define those charac­ teristics of cellular activity that permit the malignant cell to compete so effectively with the normal constituent, which ultimately Ieads to such destructive events. Although great strides have been made toward those goals, as evidenced by a number of new chapters and the new information gathered into others, and although the achievement of those goals sometimes appears but a tantalizing experiment away, none have been achieved. For example, several chapters indude descriptions of the progress that has been made toward the development of "quick assays.

The promise of chemotherapeutic control in the field of oncology seemed, in the beginning, no less bright than it had proven in the field of bacterial disease, and, therefore, its failures were felt all the more. Despite the serendipitous discoveries and inspired insights which tantalized us with striking remissions, or the rare tumors which proved to be fully susceptible to a given agent, in the main, there has been either total failure or a painfully slow acquisition of an armamentarium against a limited number of malignancies. To expect more, however, was the result of ignorance of the malignant cell, for, as has been described in the previous volumes of this series, the exploitable differences between malignant and normal cells are few or undiscovered. "Differences" is the "numerator" in this formula, but "exploitable" is the operational term, for, although a great number of differences bet\\\een normal and malignant cells have been described, rarely are these differences observed in a vital metabolic pathway or a crucial macromolecu­ lar structure. Essentially, the basic metabolic pathways and nutritional require­ ments for :lOrmal and malignant cells are the same, resulting in the fact that no chemotherapeutic agent can successfully inhibit a function in the majority of malignant cells without adversely affecting a similar function in the normal cell. It was, therefore, naive to expect a "magic bullet" which would select the malignant cell and destroy it.

The impact of basic research on oncology has been particularly impressive in the recent search for the cause of malignancy. Equally impressive is our appreciation of the cause of tumors based on observation. Even in the earliest era of the study of infectious diseases, it was proposed that tumorous growth in animals and birds resulted from "minute" infectious particles. Experiments then supported the hypothesis, that the etiologic agent in many animal tumors was viral. The development of molecular biology, supported by technical advances and conceptual understanding of macromolecular action, led to an explosive increase in studies of animal oncogenic viruses. For a decade, new findings emerged from research laboratories revealing the enormous variety of such agents, the complex­ ity of their interactions with cells, and the tantalizingly possible mechanisms by which they might cause malignant transformation of the cell. Repeatedly, clues emerged which suggested the intervention of viral agents in human tumors. A breathless excitement pervaded both the scientific and public communities as highly publicized findings rapidly followed one another. The excitement was no less scientific than it was practical, for implicit in the concept of the viral oncogen is the possibility of specific virostatic or virotoxic agents or of immunization.

As was shown in the first two volumes of this series, great strides have been made in identifying many of the agents or classes of substances responsible for carcinogenesis and in delineating their interactions with the cell. Clearly, the aim of such studies is that, once identified, these agents can be eliminated from the environment. Yet, despite these advances and the elimination of some important carcinogenic agents, one major problem exists. It is a constant monitor of all oncologic study and diminishes the importance of every experiment and of every clinical observation. As we noted earlier, that problem is our inability to define the malignant cell. It is through studies of the fundamental biology of tumors that we seek this definition. A vast amount of information has been gathered which describes what this cell does and-to a lesser extent-how it does it. But the why evades us. We have been unable to define the malignant cell, save in broad terms by comparing it to its normal counterpart. The major problem appears to be that the malignant cell does so much. It is a chimera, mystifyingly composed of normal activities and structures, of phenotypic schizophrenia with embryonic, fetal, and adult charac­ teristics and, occasionally, a hint of an unclassifiable capacity unique to malignant cells.

The history of the development of cancer therapy has been marked by a recurring pattern, one of initially exciting and encouraging results as new methods were introduced, followed by dismaying failures. The extremity of the disease and its high mortality have dictated that each means of damaging tumor cells would be rapidly explored and exploited as a mode of therapy, long before the correspond­ ing theory and technique were completely understood and perfected. Thus radiation was used as an antitumor agent almost immediately following recogni­ tion of its cytodestructive capability. Equally constant, following the rapid utilization of new therapeutic methods, has been a period of significant technical improvements. This second aspect of the pattern is also illustrated by the field of radiotherapy. New radiation sources, new methods of dosimetry, use of high-energy radiation, and other new techniques allowed the therapist to better focus upon the tumor and to improve the geometry of exposure. Thus, with each technical advance, the "reach" of radiotherapy was increased and damage to normal tissues was decreased. Inevitably, however, a limit was reached, a point at which clinicians and researchers realized they could go no further without returning to a more fundamental search, one based on the biology of the tumor cell itself.

This series of books attempts to present, in a comprehensive manner, the field of oncology divided into three major areas; etiology, biology, and therapy. These books should serve as landmarks in the rapidly expanding experimental and clinical "universe" of this field. To some, they will be introductory; to others, a summary; for all, critical comments on the futuI'e of research. In l'ecognition of the difficulties inherent in attempting to pause and reflect while experimental data emerge with ever-increasing rapidity, the presentations take the form of overviews rather than reviews. Where possible, an historical perspective on observations and experimentation which led to our present understanding is presented, the state of the art in technique and approach is reviewed, and the gaps in knowledge and in technique are indicated. The aim throughout is integration-using the findings from one approach for comparison with others. The tremendous expansion of interest in oncology as a medical-biological discipline stimulated the publication of these volumes. This expansion, well warranted in terms of the impact of oncology on human morbidity, has been characterized by at least three phenomena. First, there has been an enormous increase in money and manpower devoted to the investigation and treatment of malignancy. That the research has become more and more "directed" or program-oriented signals the interest of those beyond the scientific community in the management of the eHort. Second, increasing numbers of students are entering the field of oncology as their major training program.

Six years ago when the first edition of this volume appeared as the first of the series, questions were posed in its preface that are as valid today as they were then. In that preface, I proposed the following challenges: (1) We must identify carcinogenic agents, and by an analysis of their "nature," e. g. , structure and physical characteristics, we may better understand their mechanism of action. (2) We must identify crucial interactions between these carcinogens and impor­ tant macromolecules within the cell, distinguishing those which relate to carcinogenesis from those which are extraneous. (3) We must examine the alterations of cell function induced by these reactions, for it is with an understanding of phenotypic variation that we may know why malignant cells escape from normal homeostatic control. (4) Last, and perhaps of greatest importance, we must define malignancy--define those charac­ teristics of cellular activity that permit the malignant cell to compete so effectively with the normal constituent, which ultimately Ieads to such destructive events. Although great strides have been made toward those goals, as evidenced by a number of new chapters and the new information gathered into others, and although the achievement of those goals sometimes appears but a tantalizing experiment away, none have been achieved. For example, several chapters indude descriptions of the progress that has been made toward the development of "quick assays.

The promise of chemotherapeutic control in the field of oncology seemed, in the beginning, no less bright than it had proven in the field of bacterial disease, and, therefore, its failures were felt all the more. Despite the serendipitous discoveries and inspired insights which tantalized us with striking remissions, or the rare tumors which proved to be fully susceptible to a given agent, in the main, there has been either total failure or a painfully slow acquisition of an armamentarium against a limited number of malignancies. To expect more, however, was the result of ignorance of the malignant cell, for, as has been described in the previous volumes of this series, the exploitable differences between malignant and normal cells are few or undiscovered. "Differences" is the "numerator" in this formula, but "exploitable" is the operational term, for, although a great number of differences bet\\\een normal and malignant cells have been described, rarely are these differences observed in a vital metabolic pathway or a crucial macromolecu­ lar structure. Essentially, the basic metabolic pathways and nutritional require­ ments for :lOrmal and malignant cells are the same, resulting in the fact that no chemotherapeutic agent can successfully inhibit a function in the majority of malignant cells without adversely affecting a similar function in the normal cell. It was, therefore, naive to expect a "magic bullet" which would select the malignant cell and destroy it.

The impact of basic research on oncology has been particularly impressive in the recent search for the cause of malignancy. Equally impressive is our appreciation of the cause of tumors based on observation. Even in the earliest era of the study of infectious diseases, it was proposed that tumorous growth in animals and birds resulted from "minute" infectious particles. Experiments then supported the hypothesis, that the etiologic agent in many animal tumors was viral. The development of molecular biology, supported by technical advances and conceptual understanding of macromolecular action, led to an explosive increase in studies of animal oncogenic viruses. For a decade, new findings emerged from research laboratories revealing the enormous variety of such agents, the complex­ ity of their interactions with cells, and the tantalizingly possible mechanisms by which they might cause malignant transformation of the cell. Repeatedly, clues emerged which suggested the intervention of viral agents in human tumors. A breathless excitement pervaded both the scientific and public communities as highly publicized findings rapidly followed one another. The excitement was no less scientific than it was practical, for implicit in the concept of the viral oncogen is the possibility of specific virostatic or virotoxic agents or of immunization.

As was shown in the first two volumes of this series, great strides have been made in identifying many of the agents or classes of substances responsible for carcinogenesis and in delineating their interactions with the cell. Clearly, the aim of such studies is that, once identified, these agents can be eliminated from the environment. Yet, despite these advances and the elimination of some important carcinogenic agents, one major problem exists. It is a constant monitor of all oncologic study and diminishes the importance of every experiment and of every clinical observation. As we noted earlier, that problem is our inability to define the malignant cell. It is through studies of the fundamental biology of tumors that we seek this definition. A vast amount of information has been gathered which describes what this cell does and-to a lesser extent-how it does it. But the why evades us. We have been unable to define the malignant cell, save in broad terms by comparing it to its normal counterpart. The major problem appears to be that the malignant cell does so much. It is a chimera, mystifyingly composed of normal activities and structures, of phenotypic schizophrenia with embryonic, fetal, and adult charac­ teristics and, occasionally, a hint of an unclassifiable capacity unique to malignant cells.

The history of the development of cancer therapy has been marked by a recurring pattern, one of initially exciting and encouraging results as new methods were introduced, followed by dismaying failures. The extremity of the disease and its high mortality have dictated that each means of damaging tumor cells would be rapidly explored and exploited as a mode of therapy, long before the correspond­ ing theory and technique were completely understood and perfected. Thus radiation was used as an antitumor agent almost immediately following recogni­ tion of its cytodestructive capability. Equally constant, following the rapid utilization of new therapeutic methods, has been a period of significant technical improvements. This second aspect of the pattern is also illustrated by the field of radiotherapy. New radiation sources, new methods of dosimetry, use of high-energy radiation, and other new techniques allowed the therapist to better focus upon the tumor and to improve the geometry of exposure. Thus, with each technical advance, the "reach" of radiotherapy was increased and damage to normal tissues was decreased. Inevitably, however, a limit was reached, a point at which clinicians and researchers realized they could go no further without returning to a more fundamental search, one based on the biology of the tumor cell itself.