Possible etiologic mechanisms in chemical carcinogenesis

Some highlights in the development of our knowledge about carcinogens as etiological agents for cancer are reviewed briefly. Advances during the past 20 years relating to metabolic activation with the genesis of reactive metabolites, molecular targets and their interactions with activated carcinogens, oncogenes as molecular targets and the dependence on cell proliferation, all relating to the initiation process, are reviewed. Critical to initiation is the new phenotype in the initiated cell, known only in one instance, the rat liver, in which the characteristic change is one of resistance to many xenobiotic influences. The need for clonal expansion of initiated cells as essential for carcinogenic effects is discussed. Differential inhibition has been shown as a dominant mechanistic pattern in the liver. In other systems, the manner in which clonal expansion is achieved is not evident. The need for studies of the processes involved in carcinogenesis, as well as the agents, is emphasized, in view of the continuing validity of the cell concept as the key to integrating the increasingly large volume of data from the molecular with the biological.