Transgenic and Knockout Mice as Models of Carcinogenesis

29 May

With the advent of the development  of transgenic  animals as well as gene targeting  in mice (Chapter 5), recent efforts have been directed toward the development  of animal models with specific  genetic  alterations  that make them more susceptible  to carcinogenesis  by external agents. As noted from Table 13.4, the most popular of these are mice exhibiting one defective allele of the p53 tumor suppressor gene and a transgenic mouse line (TG·AC) carrying a v-Ha- ras oncogene  fused to a zeta globin promoter.  A high frequency  of a variety of spontaneous neoplasms develop in p53-deficient mice. The incidence of such tumors is noted in Figure 13.10. In general, all of the homozygous p53-defective mice develop neoplasms by 10 months of age, while the heterozygous mice have a 50% incidence by 18 months, with over 90% incidence by 2 years of age (Donehower, 1996). However, the heterozygous animals did not show an acceler- ated carcinogenesis  of the liver, even when hepatocarcinogens  were administered  (Dass et al.,1999). In addition to this model system, which mimics the Li-Fraumeni  syndrome in humans (Chapter 5), a large number of other gene-targeted mutations have been developed in mice but have not yet been utilized  as model  systems  for identifying  potential  carcinogenic  agents (Rosenberg, 1997).

The TG·AC transgenic mouse is one of a large number of potential transgenic mice and rats that might be considered for the study of the development of neoplasia in response to test agents. However, in most cases the expression of the transgene is targeted to a specific tissue, and thus one deals with a tissue-specific  development  of neoplasia  (cf. Goldsworthy  et al.,1994). The TG·AC transgenic mouse is very effective in the identification of potential promoting agents for the skin. Administration  of the well-known skin-promoting  agent, TPA (Chapter 7), could induce the development of papillomas after only three to ten applications (Spalding et al.,1993). These investigators also studied several other potential promoting and progressor agents,

Figure 13.10 Tumor incidence of p53–/–  and p53+/–  mice. The relative frequency of each of the types of neoplasms is indicated by the proportionate size of the pie slice. (From Donehower, 1996, with permission of the author and publisher.)

all of which exhibited a short latency period and high incidence of papilloma induction. Thus, it is apparent that each of these genetic models of carcinogenesis has a role to play in the identifi- cation of potential carcinogenic agents. It will require considerable effort to validate each of the models with respect to tissue-specific carcinogenesis by complete carcinogens or by promoting and/or progressor agents (cf. Tennant, 1998).

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