Multistage Models of Neoplastic Development

29 May

As previously noted, the original studies on multistage models of carcinogenesis were developed with the epidermis of the mouse (Chapter 7). It was not until some 40 years after those initial experiments that there was some attempt at standardization of the multistage model of carcino- genesis  in mouse skin for the analysis  of the carcinogenic  potential  of specific  chemicals (Pereira, 1982). The format for such assays was essentially that described in Chapter 7 (Figure 7.1). Few refinements in the procedure were added with the exception of the use of a genetically susceptible strain of mice, the SENCAR strain, which is now utilized in such tests (Slaga, 1986). This system may also be extended to the potential analysis of progressor agents (Hennings et al.,1993; Warren et al., 1993).

Considerably  later than the initial reports of the mouse skin system, Hicks et al. (1975) demonstrated  the cocarcinogenic  or promoting action of several agents in the development  of bladder cancer in the rat. Subsequently,  other promoting agents have been demonstrated  with this or a related assay, some of which appear to be relatively unique to this tissue for both ana- tomical and chemical reasons (Cohen and Lawson, 1995; Ito and Fukushima, 1989). At about the same time as the initial report of the multistage bladder model of carcinogenesis, Peraino and associates (1977) reported a multistage model of carcinogenesis in the rat liver. This finding has led to the development of a number of models of multistage carcinogenesis in the rat liver. Solt and Farber (1976) reported a model somewhat analogous to that of Ito and colleagues, but with an aim directed primarily at studying mechanisms of hepatocarcinogenesis  rather than utilizing it as an assay system for potential carcinogens. Shortly thereafter, Pitot et al. (1978) developed a model wherein initiation was performed with a nonnecrogenic dose of the initiating agent, sub- sequently followed by chronic administration  of a promoting  agent. The format of these two assay systems are noted in Figure 13.9. The end point of these systems is the quantitative analy- sis of altered hepatic foci measured by one of several enzymatic markers, the most sensitive be- ing the expression  of GST-P (Hendrich  et al., 1987). Several  studies have investigated  the potential for such analyses in the detection of chemical carcinogens (Pereira and Stoner, 1985; Williams, 1989; Oesterle and Deml, 1990). A similar format has been used to study the preneo- plastic aberrant crypt foci in the colon of animals administered potential carcinogens (Ghia et al., 1996). However, as yet all such assays utilizing preneoplastic end points have not found gen- eral usefulness  in the identification  of potential carcinogenic  agents. It is possible that in the future such assays may be useful in distinguishing  between agents exerting their carcinogenic effect primarily at one or another of the stages of carcinogenesis.

Figure 13.9 Formats of short-term  models of multistage  hepatocarcinogenesis in the rat. A. The Solt- Farber  model,  in which  animals  are administered  a necrogenic  dose of diethylnitrosamine  followed  2 weeks later by the administration  of 0.02% acetylaminofluorene (shaded bar) with a 70% partial hepatec- tomy performed after 1 week of AAF feeding and sacrifice 1 week following the surgery. B. The Pitot et al. (1978) model, in which a non-necrogenic  dose (10 mg/kg) of DEN is administered 24 hours after a partial hepatectomy  (PH), and animals are fed a normal diet for 8 weeks, at which time they are placed on a diet containing 0.05% phenobarbital for a subsequent 24 weeks and then sacrificed. The end point of both mod- els is the quantitation of altered hepatic foci.

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