With the division of the process of carcinogenesis into at least three distinct and sequential stages, it now becomes possible to place carcinogenic agents into various categories depending on their effecting one or more of the stages of initiation, promotion, and progression. Such a classification is given in Table 9.10. Agents that are capable of initiation and thus are true in- complete carcinogens are very rare if they exist at all. The “pure” initiating activity of certain chemicals in specific tissues has been reported (cf. DiGiovanni, 1992); but in most instances, at higher doses or in different tissues, such agents can be shown to be carcinogenic, usually acting as complete carcinogens. On the other hand, as we have seen from the experimental basis for a distinction between initiation and promotion, very low doses of complete carcinogens will act to initiate cells but cannot sustain the remainder of the carcinogenic process. This consideration is undoubtedly very important in carcinogenesis in the human, where most exposures to a carcino- genic agent are at extremely or relatively low levels. The list of promoting agents and putative promoting agents is, like complete carcinogens, growing steadily. Progressor agents in the strict sense of inducing the characteristics noted in Table 9.2 have been only tentatively identified (Ta- ble 9.2). Some agents, specifically initiating and progressor agents, possess as a primary aspect of their carcinogenic mechanism the ability to alter the structure of DNA and/or chromosomes. Such “genotoxic” effects of these agents have been linked directly to the induction of neoplasia. However, a number of chemicals when administered chronically to animals induce the develop- ment of neoplasia, but there is no evidence of their direct “genotoxic” action on target cells. Considering the effects of chemicals on the development of neoplasia via a multistage process, one may classify such agents as promoting agents acting to expand clones of spontaneously ini- tiated cells. The consequent selective enhancement of cell replication in such initiated cell clones sets the stage for the spontaneous transition of an occasional cell into the stage of pro- gression, as discussed above. However, this explanation of “nongenotoxic” carcinogenesis is likely to be oversimplified. Specifically, Tennant (1993) has demonstrated that, in a large series of whole-animal bioassays for carcinogenesis (Chapter 13), the frequencies of induced neoplasia by nonmutagenic carcinogens does not correlate well with the spontaneous rates of neoplastic development in a variety of tissues in control animals. A number of potentially indirect mecha- nisms for the action of nongenotoxic carcinogens—such as induction of oxidative stress, the per- manent but nonmutagenic alteration of gene expression, or enhancement of intrachromosomal recombination (Schiestl, 1989)—may contribute to mechanisms involved in this process. Table
Table 9.10 Classification of Chemical Carcinogens in Relation to Their Action on One or More Stages of Carcinogenesis
Initiating agent (incomplete carcinogen)—a chemical capable only of initiating cells Promoting agent—a chemical capable of causing the expansion of initiated cell clones Progressor agent—a chemical capable of converting an initiated cell or a cell in the stage of promotion to a potentially malignant cell Complete carcinogen—a chemical possessing the capability of inducing cancer from normal cells, usually possessing properties of initiating, promoting, and progressor agents
9.11 lists a representative sample of chemicals that are nonmutagenic as assessed by induction of mutations in bacteria or mammalian cells but which, on chronic administration, are carcinogenic in experimental systems. As indicated in the table, a number of these chemicals have been shown to be promoting agents, but some are not. Several of those that are not promoting agents may be classified as putative progressor agents, as evidenced by their effectiveness as clastogens in experimental systems (Table 9.2). A number of other chemicals (Tennant, 1993) have not been tested for their action at specific stages of carcinogenesis and thus cannot neatly be placed into the classification of Table 9.11.
Along with other mechanisms, agents that are not mutagenic or genotoxic may induce di- rect toxicity, with sustained tissue damage and subsequent cell proliferation. Both direct DNA damage and increased cell proliferation may lead to clastogenesis (Scott et al., 1991). The cell proliferation resulting from toxicity may selectively induce enhanced replication of an already damaged genome in the initiated cell population (Larson et al., 1994). Thus, while cell toxicity does not directly induce carcinogenesis, it is capable of indirectly enhancing the process (Brad- ley et al., 1987; Grasso et al., 1991). Since many agents that are tested at chronic doses induce at least a mild degree of toxicity, it has been argued that the format of the testing system leads to the induction of neoplasia. Thus, neoplastic development observed with the administration of test compounds may result from enhanced cell proliferation due to toxicity, associated with chronic high doses utilized, rather than from a direct carcinogenic effect of the agent (Ames and Gold, 1990b). However, several types of nonmutagenic chemical carcinogens have primarily a tumor-promoting type of effect, including agents that induce P450s, other mitogenic agents, and cytotoxic agents as well as many that act through receptor-mediated processes.