In a general sense, all carcinogenic agents may be considered exogenous modifiers of carcino- genesis. However, below are discussed the effects of specific agents and processes not usually considered to be carcinogenic as exogenous modifiers of the various stages of carcinogenesis. Here it becomes obvious that, because of the characteristics of the stage of tumor promotion in its responsiveness to environmental factors, both endogenous and exogenous, most exogenous agents affecting carcinogenesis appear to act at the stage of tumor promotion. Furthermore, agents exhibiting promoting activity may also inhibit the effect of some carcinogens when given prior to or concomitant with a complete carcinogen or an initiating agent (Chapter 7).
Effects of Drugs and Other Agents and Procedures on the Stages of Carcinogenesis
Earlier in this chapter, it was already noted that changes in hormones can alter the process of carcinogenesis, probably through their effects on the stage of promotion. However, in view of the requirement for the metabolism of many complete carcinogenic agents to a reactive form, which is probably the actual initiating agent, modifications of the metabolic activation by exoge- nous agents may lead to alterations in the efficiency and/or repair of the initiation process. In Chapter 3, the effect of the administration of mixtures of carcinogenic agents was briefly consid- ered. The discussion here focuses on the effect of combining carcinogenic agents, which can result in an enhancement or synergistic effect or, conversely, an inhibitory or antagonistic effect.
In a recent review, Berger (1995) used the term synergism when a combination of carcinogens exerts an effect exceeding the arithmetic sum of the effects of the chemicals individually. In the extreme, combinations of chemicals each at a specific dose may be carcinogenic while each chemical administered individually at the same dose is noncarcinogenic. Antagonism is defined as the combination of carcinogens exerting an effect less than additive or even lower than the effect of one of the carcinogens singly. Berger (1995) has reviewed a number of the synergistic and antagonistic effects of binary and ternary mixtures of chemical carcinogens. The variables associated with the carcinogenic effect of combinations of chemicals are multiple, including the sequence of the administration of the individual chemicals, the toxicity of one or more of the members of the mixture at the doses employed, and the organ specificity of the individual agents. In some instances, combinations of carcinogens led to the development of neoplasms of tissues that are not usually induced by either of the agents employed (cf. Newberne and Connor,
1980). In an earlier study, Berger et al. (1987) administered to rats a mixture of three different carcinogenic nitrosamines, each at doses that were not carcinogenic when given alone. The mix- ture was carcinogenic. In a series of studies by Ito and colleagues (Takayama et al., 1989; Fuku- shima et al., 1991; Uwagawa et al., 1991), the administration of up to 40 carcinogenic agents or multiple mixtures of carcinogenic with noncarcinogenic agents resulted, as expected, in a vari- ety of effects, both synergistic and additive, but no attempt at determining mechanisms was un- dertaken with these extremely complex experiments. In some instances, a change in the solvent in which the carcinogenic agent is applied to tissues such as skin may enhance the carcinogenic action of such an agent, e.g., specific polycyclic hydrocarbons (Warshawsky et al., 1993). While the toxicity of one or more components of the mixture may tend to inhibit the carcinogenic ef- fect of the mixture, in other instances, especially in hepatocarcinogenesis, toxicity results in an enhancement of the proliferative activity of hepatocytes, thereby enhancing the carcinogenic ac- tion of carcinogenic agents even at low doses (Taylor et al., 1974; Pitot et al., 1978). Enhancing effects of the hepatoproliferative agent α-hexachlorocyclohexane have been demonstrated with several hepatocarcinogens (Schulte-Hermann and Parzefall, 1981).
Chemical inhibition of carcinogenesis has been most extensively studied during hepato- carcinogenesis. The carcinogenic action of some nitrosamines and azo dyes is inhibited by the prior or simultaneous administration of carcinogenic polycyclic hydrocarbons, the latter not usu- ally considered as complete carcinogens for the liver (cf. Venkatesan et al., 1970). The inhibition of azo dye hepatocarcinogenesis by benzimidazole derivatives such as chloramphenicol and di- ethylstilbesterol (Akao and Kuroda, 1978; Blunck et al., 1971/1972) gives further examples of this inhibition. A most likely mechanism for the inhibition of carcinogenesis of the liver by these agents is their effect on altering the metabolism of the carcinogen and inhibiting the formation of reactive metabolites (Berger, 1995). Both β-naphthoflavone and pregnenolone-16α-carbonitrile are inducers of xenobiotic metabolism and inhibitors of hepatocarcinogenesis induced by dime- thylnitrosamine (Argus et al., 1978). In other tissues, chloroform administration inhibits 1,2- dimethylhydrazine-induced gastrointestinal tract neoplasms in rats (Daniel et al., 1989), while some polycyclic hydrocarbons that are noncarcinogenic or weakly carcinogenic inhibit initiation of epidermal carcinogenesis by DMBA or benzo[a]pyrene (cf. Berger, 1995). Inhibition of hepa- tocarcinogenesis by azo dyes can also be accomplished by surgical alteration of the blood supply of the liver to produce a portacaval anastomosis, that is, diversion of the portal blood supply from the liver to the systemic circulation via the vena cava (Ricco et al., 1977). Thus, one can appreciate that the addition of agents or procedures to simple carcinogenic experiments may produce a variety of alterations in the process of carcinogenesis, especially experimental hepato- carcinogenesis. While many of these agents act to alter the stage of initiation, others may affect the stages of promotion and/or progression. The next section shows a similar complexity of di- etary effects on carcinogenesis.
Dietary Factors Influencing Stages of Carcinogenesis
One of the major exogenous modifiers of carcinogenesis is diet (cf. Rogers et al., 1993). Effec- tors of such modification include the caloric content of the diet; its major constituents, such as protein, lipid, and carbohydrate; and trace factors in the diet such as various vitamins, minerals, and contaminants. Dietary contaminants, where their identity is known, may exert direct carci- nogenic effects. Examples of such are aflatoxin B1, lipid peroxides, and toxic metals. Since these
are covered in other sections, the composition of the diet in relation to normal constituents is