Nakahara Memorial Lecture. Chemical carcinogenesis and its prevention: is there a common denominator?

Chemical carcinogenesis is generally recognized as a multistep process consisting of initiation, promotion and progression. Today there is substantial evidence that the process involves reactive species of oxygen, which are generated through enzymic or nonenzymic transformation of xenobiotics and their metabolites, and which can alter nucleic acids, proteins, and lipids, thereby interfering with normal cell growth and differentiation. Most cells possess powerful defense mechanisms against these effects, both in the form of antioxidants acting as free-radical scavengers, and of various enzymes capable of preventing the formation of facilitating the removal of reactive species of oxygen. The present paper is a brief survey of current knowledge concerning these mechanisms. The available information is consistent with the concept that chemical carcinogenesis and its prevention share a common denominator, namely, the metabolic activation of a xenobiotic that can lead, on one hand, to the generation of reactive species of oxygen and thereby cancer initiation, promotion and progression, and, on the other hand, to an induction of antioxidant enzymes that can prevent these effects. The final outcome will depend on the relative impact of the two events. Elucidation of the underlying molecular mechanisms may provide a rationale for devising drugs that enhance resistance against chemical carcinogenesis without themselves being carcinogenic.