Chemical carcinogenesis: a biochemical overview

In principle, it is possible to identify and eliminate chemicals in our environment that cause cancer, but practical considerations make it very difficult to achieve this goal. Since we will be exposed to carcinogens for some time to come, we must try to understand how known carcinogens work at the molecular level if we are to develop more rational approaches for preventing their action. This knowledge is also important if we are to proceed logically in developing better procedures for early diagnosis and treatment. Since somatic cell mutations produced by exposure to chemical carcinogens represent key events in the initiation of tumors, we must try to understand which genes are involved, what kind of mutations trigger transformation and how carcinogens produce these alterations of DNA. In this paper I discuss metabolic activation of chemicals to produce carcinogens that react with DNA, consider repair of the covalent adducts that are produced when carcinogens react with DNA, and point out some key questions that must be answered before we can understand how carcinogens work. Then I outline some recent progress in the molecular biology of human oncogenes and indicate how we are using site-specific mutagenesis in preselected codons of the c-Ha ras protooncogene in an attempt to define which carcinogen-induced DNA adducts transform normal protooncogenes into active oncogenes.