Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules

Studies on a variety of chemical carcinogens have demonstrated that their ultimate reactive and carcinogenic forms are strong electrophiles. Some carcinogens, such as alkylating agents, are in their ultimate forms as administered, but most require metabolism to these active derivatives. The ultimate carcinogens react, usually non‐enzymatically, with nucleophilic constituents in vivo. Of particular interest in regard to their possible importance in carcinogenesis have been the covalent interactions of these electrophilic reactants with cellular informational macromolecules, the DNAs, RNAs, and proteins. Current data are consistent with the idea that the initiation step of chemical carcinogenesis is a mutagenic event and is caused by alteration of DNA by the ultimate carcinogens. The nature of the carcinogen metabolite(s) involved in the promotion phase has not been determined, but there appears to be no requirement that they be electrophilic. The development of the concept of ultimate chemical carcinogens as strong electrophilic reactants is reviewed, especially with respect to the studies carried out in the authors' laboratory.