* American Health Foundation, Naylor Dana Institute, One Dana Road, Valhalla, New York 10595; and
New York Medical College, Environmental Pathology and Toxicology, Program on Medicine, Food, and Chemical Safety, Valhalla, New York 10595
Received September 3, 1999; accepted September 7, 1999
Much progress has been made in the understanding of the mechanisms of carcinogenesis in the last 50 years. Early studies identified macromolecular binding of carcinogens first to protein (Miller and Miller, 1953; Weisburger and Weisburger, 1958
), then to RNA (Marroquin and Farber, 1965
). Subsequently, methods to isolate DNA from cells became available, and Watson and Crick provided information about the molecular structure of DNA, which opened the possibility to examine the hypothesis that cancer stemmed from a somatic mutation. Szafarz and Weisburger (1969) and Matsushima and Weisburger (1969) carefully investigated radioactivity from 14C-labeled 2-acetylaminofluorene in liver proteins, RNA, and DNA as a function of certain inhibitors of carcinogenesis. They found that the binding to protein or to RNA did not correlate with inhibition, but that reduced DNA binding reliably reflected the biological effect. In addition, they examined the stability of label attached to DNA and found a triphasic decline, perhaps early evidence of DNA repair, and stability of adducts at specific sites on the DNA bases.
As interest increased in effects of carcinogens on DNA, a conference was held in Skokloster, Sweden on Evaluation of Genetic Risks of Environmental Chemicals, the proceedings of which were published (Ramel, 1973). A working group chaired by Lars Ehrenberg, and consisting of Peter Brookes of London, Hermann Druckrey of Freiburg, Germany, Bengt Lagerlöf of Stockholm, Jack Litwin of Stockholm, and Gary Williams, then a visiting fellow at the Wenner-Gren Institute in Stockholm, addressed "The Relation of Cancer Induction and Genetic Damage." It was Professor Druckrey who suggested the following text: "In order to describe the components of chemical interaction with genetic material, the term genotoxic is proposed as a general expression to cover toxic, lethal and heritable effects to karyotic and extra-karyotic genetic material in germinal and somatic cells."
This formulation was entirely appropriate as the association between mutagenicity in various prokaryotic and eukaryotic systems and carcinogenicity began to be established. In fact, in 1970 and 1971, Weisburger, who was impressed with the term genotoxic as a likely indicator of human cancer risk, organized two workshops chaired by A. Hollaender of the Oak Ridge National Laboratory. Recommendations made encouraged Weisburger to develop a National Cancer Institute contract program to enlarge the database by using a number of techniques to study mutational events associated with the then-known chemical carcinogens belonging to various classes and types (Weisburger, 1999). The results of this program were published in the Journal of the National Cancer Institute (62:833926, 1979). In addition, Bruce Ames (1971) initiated research on the mutagenicity of a series of known carcinogens in the reverse mutation assay in Salmonella typhimurium, which he originated in the early 1970s and which came to be known as the Ames test ( McCann et al., 1975
; Ramel et al., 1986
).
The development of a variety of techniques ensued for measuring carcinogen interaction with DNA, including binding of radiolabeled chemical, the reliable and predictive hepatocyte DNA repair assay (Williams et al., 1989), alkaline elution (Fornace et al., 1976
), and the 32P-postlabeling method of Randerath and Gupta (Reddy et al., 1984
). These procedures have established that certain classes of carcinogen are DNA reactive, i.e., genotoxic (see Fig. 1
). Conversely, a substantial number of carcinogens was found to lack genotoxicity and this knowledge was embodied in a key distinction between genotoxic and epigenetic carcinogens based on the underlying mechanism of action, as seen in Figure 1
(Weisburger and Williams, 1981
). A detailed assignment of carcinogens to these categories was elaborated in Casarett and Doull's classic monograph (see first 4 editions; Amdur et al., 1991).
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NOTES
1 To whom correspondence should be addressed. Fax: (914) 592-6317. E-mail: john_weisburger{at}nymc.edu.
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