Mechanism-based cancer prevention approaches: Targets, examples, and the use of transgenic mice

Humans are exposed to a wide variety of carcinogenic insults, including end ogenous and man-made chemicals, radiation, physical agents, and viruses. Th e ultimate goal of carcin genesis research is to elucidate the processes in volved in the induction of human cancer so that interventions may be develo ped to prevent the disease, either in the general population or in suscepti ble subpopulations. Progress to date in the carcinogenesis field, particula rly regarding the mechanisms of chemically induced cancer, has revealed sev eral points along the carcinogenesis pathway that may be amenable to mechan ism-based prevention strategies. The purpose of this review is to examine t he basic mechanisms and stages of chemical carcinogenesis, with an emphasis on ways in which preventive interventions can modify those processes. Poss ible ways of interfering with tumor initiation events include the following : i) modifying carcinogen activation by inhibiting enzymes responsible for that activation or by direct scavenging of DNA-reactive electrophiles and f ree radicals; ii) enhancing carcinogen detoxification processes by altering the activity of the detoxifying enzymes; and iii) modulating certain DNA r epair processes. Possible ways of blocking the processes involved in the pr omotion and progression stages of carcinogenesis include the following: i) scavenging of reactive oxygen species; ii) altering the expression of genes involved in cell signaling, particularly those regulating cell proliferati on, apoptosis, and differentiation; and iii) decreasing inflammation. In ad dition, the utility for mechanism-based cancer prevention research of new a nimal models that are based on the overexpression or inactivation of specif ic cancer-related genes is examined.