Text: Inducers of DNA Repair. There are three possible chemopreventive mechanisms that involve DNA repair (70,71). The first is an increase in the overall level of DNA repair. An example of a naturally occurring chemical that increases the level of DNA repair is vanillin, which inhibits mammalian cell mutagenicity (72). The mechanisms through which vanillin promotes DNA repair have not been determined. Second, the enzyme poly(ADP-ribosyl)transferase (ADPRT) is involved in modulation of DNA damage (73,74), and the level of this enzyme is reduced by chemical carcinogens (75). N-Acetylcysteine prevents the decrease in ADPRT caused by the carcinogen 2-acetylaminofluorene (AAF) (75). The third mechanism is suppression of error-prone DNA repair. Protease inhibitors depress error-prone repair in bacteria (76), and it has been suggested that they could prevent carcinogenesis by inhibiting an error-prone repair system activated by proteases that, in turn, are induced by tumor promoters (77). Many would argue that the use of blocking agents is not a feasible approach to chemoprevention in humans, since all members of high risk groups have presumably received some exposure to initiating agents. The work of Vogelstein et al. (78) and Fearon and Vogelstein (79) on colorectal cancer, however, indicates that human cancer is not adequately represented by the traditional initiation/promotion model, but more likely involves an accumulation of mutational events in key genes such as the oncogenes and tumor suppressor genes. If that is so, then administration of blocking agents should prove of some value, since many individuals at high risk (e.g., smokers and the occupationally exposed) are continually exposed to genotoxic carcinogens. Moreover, it could also be important to inhibit further mutational events in individuals who have a reduced exposure to carcinogens but remain at higher risk for cancer development (e.g., former tobacco smokers). Individuals who are genetically predisposed to cancer must avoid further mutational events that could trigger the carcinogenesis process; such individuals are excellent candidates for prophylactic treatment with blocking agents. Also, the administration of inhibitors of promotion/progression will be helpful in combating the effects of exposure to a wide range of carcinogens, no matter what model human carcinogenesis follows. Co-administration of blocking and suppressing agents is a promising strategy for optimizing efficacy.

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