Advances in Chemical Carcinogenesis: A Historical Review and Prospective

Abstract

The American Association for Cancer Research has been the citadel for communicating research on chemical carcinogens for over a century. It therefore seems appropriate that a review of chemical carcinogenesis inaugurates a series of articles highlighting advances in understanding, treating, and preventing cancer.At the dawn of the 20th century, we had recognized that chemicals cause cancer, but we had not yet identified individual cancer-causing molecules, nor did we know their cellular targets. We clearly understood that carcinogenesis, at the cellular level, was predominantly an irreversible process. What we lacked was knowledge of the mechanisms by which chemicals cause cancer and the molecular changes that characterize tumor progression.We now are early in a century in which cancer is being investigated at the molecular level, and we have developed technologies that afford unprecedented power to delineate and manipulate altered pathways in cancer cells. Can we harness new insights and technologies to prevent or obliterate human cancers or delay their progression? Can we identify individuals who have a particularly high susceptibility to specific environmental carcinogens?The history of chemical carcinogenesis is punctuated by key epidemiologic observations and animal experiments that identified cancer-causing chemicals and that led to increasingly insightful experiments to establish molecular mechanisms and to reduction of human exposure. In 1914, Boveri (1) made key observations of chromosomal changes, including aneuploidy. His analysis of mitosis in frog cells and his extrapolation to human cancer is an early example of a basic research finding generating an important hypothesis (the somatic mutation hypothesis). The first experimental induction of cancer in rabbits exposed to coal tar was performed in Japan by Yamagiwa and Ichikawa (2) and was a confirmation of Pott's epidemiologic observation of scrotal cancer in chimney sweeps in the previous century (Fig. 1; ref. 3). Because coal tar is a complex mixture of chemicals, a search for specific chemical carcinogens was undertaken. British chemists, including Kennaway (4), took on this challenge and identified polycyclic aromatic hydrocarbons, for example, benzopryene, which was shown to be carcinogenic in mouse skin by Cook, Hewett, and Hieger in 1933 (5). The fact that benzopyrene and many other carcinogens were polyaromatic hydrocarbons lead the Millers (6) to postulate and verify that many chemical carcinogens required activation to electrophiles to form covalent adducts with cellular macromolecules. This in turn prompted Conney and the Millers (7) to identify microsomal enzymes (P450s) that activated many drugs and chemical carcinogens.The discovery of DNA as the genetic material by Avery, MacLeod, and McCarthy (8) and the description of the structure of DNA by Watson and Crick (9) indicated that DNA was the cellular target for activated chemical carcinogens and that mutations were key to understanding mechanisms of cancer. This led to defining the structure of the principal adducts in DNA by benzo(a)pyrene (10) and aflatoxin B1 (11). The concepts developed in investigating mechanisms of chemical carcinogenesis also led to discoveries that are relevant to other human conditions in addition to cancer, including atherosclerosis, cirrhosis, and aging.Global epidemiologic studies have indentified environmental and occupational chemicals as potential carcinogens. The most definitive epidemiologic studies have been those in which a small group is exposed to an inordinately large amount of a specific chemical, such as aniline dyes.Figure 1 illustrates exposure of individuals to residues from fossil fuel in chimneys, to tobacco smoke, and to fungi containing aflatoxin, and the identification of the responsible carcinogen(s). Active smoking and exposure to second-hand smoke are among the major causes of cancer mortality worldwide. Even after causative chemicals are identified, however, measurement of accumulated exposure of individuals in different environments remains an important challenge.The fact that genetic changes in individual cancer cells are essentially irreversible and that malignant changes are transmitted from one generation of cells to another strongly points to DNA as the critical cellular target modified by tobacco smoke and environmental chemicals. DNA damage by chemicals occurs randomly; the phenotypes of associated carcinogenic changes are determined by selection.Cancers caused by environmental agents frequently occur in tissues with the greatest surface exposure to the agents: lung, gastrointestinal tract, and skin. Recently, the study of chemical carcinogenesis has merged with studies on the molecular changes in cancer cells, thus generating biological markers to assess altered metabolic pathways and providing new targets for therapy. Although these are exciting areas, they may be peripheral to attacking the primary causes of the most c