In Vivo Transgenic Bioassays and Assessment of the Carcinogenic Potential of Pharmaceuticals

Abstract

There is general agreement in the scientific community on the need to improve carcinogenicity testing and the assessment of human carcinogenic risk and to incorporate more information on mechanisms and modes of action into the risk assessment process. Advances in molecular biology have identified a growing number of genes such as protooncogenes and tumorsuppressor genes that are highly conserved across species and are assocjated with a wide variety of human and animal cancers. In vivo transgenic rodent models incorporating such mechanisms are used to identify mechanisms involved in tumor formation and as selective tests for carcinogens. Transgenic methods can be considered an extension of genetic manipulation by selective breeding, which long has been employed in science and agriculture. The use of two rodent species in carcinogenicity testing is especially important for identifying transspecies carcinogens. The capacity of a substance to induce neoplasia across species suggests that the mechanism(s) involved in the induction of the neoplasia are conserved and therefore may have significance for humans. Based on available information there is sufficient experience with some in vivo transgenic rodent carcinogenicity models to support their application as complementary second species studies in conjunction with a single 2-year rodent carcinogenicity study. The optional substitution of a second 2-year rodent carcinogenicity study with an alternative study such as an in vivo transgenic carcinogenicity study is part of the International Conference on Harmonization guidance Si B: Testing for Carcinogenicity of Pharmaceuticals. This guidance is intended to be flexible enough to accommodate a wide range of possible carcinogenicity assessment models currently under consideration or models that may be developed in the future. The use of an in vivo transgenic mouse model in place of a second 2-year mouse study will improve the assessment of carcinogenic risk by contributing insights into the mechanisms of tumorigenesis and potential human relevance not available from a standard 2-year bioassay. It is envisioned that this will stimulate the further development of more efficient and relevant methods for identifying and assessing potential human carcinogenic risk, which will benefit public health.Environ Health Perspect 106(Suppl 1): 71-80 (1998). http.//ehpnet1.niehs.nih.gov/ docs/1998/Suppl-1/71-80contrera/abstract.html

Is p53 Haploinsufficient for Tumor Suppression? Implications for the p53+/- Mouse Model in Carcinogenicity Testing

“…An oligonucleotide containing the p53 consensus binding site was bound by p53 in tumor extracts from p53 / tumors retaining p53, HAPLOINSUFFICIENCY IN THE p53 / MODEL 149 FIGURE 1.-Tumor incidence and spectra in p53-de cient mice and their wild-type littermates. Mice de cient for p53 (p53 / and p53 / ) and wild-type for p53 (p53 / ) of mixed inbred C57BL/ 6 129/Sv background were monitored for tumors and longevity over a period of 3 years as previously described (2,3,10). Moribund mice or mice displaying overt tumors were sacri ced and examined by necropsy.…”

“…In the last several years, the p53 / mice have been extensively tested for carcinogen sensitivity in 6-month bioassays (2,3,8,12,28,30). It has been proposed that the 6 month p53 / carcinogenicity assay could substitute for 1 of the 2-year rodent bioassays currently required for pharmaceutical licensing by the U.S. Food and Drug Administration (3,15).…”

“…It has been proposed that the 6 month p53 / carcinogenicity assay could substitute for 1 of the 2-year rodent bioassays currently required for pharmaceutical licensing by the U.S. Food and Drug Administration (3,15). The accumulated data, discussed in more detail elsewhere in this volume, indicate that p53 / mice are generally sensitive to known genotoxic carcinogens within the six-month time frame, but are insensitive to nongenotoxic carcinogens and noncarcinogens (12,28,31).…”

The Tg rasH2 Mouse in Cancer Hazard Identification

“…Based on the results of these power simulations, the authors recommend using 20 to 25 mice/sex/group for 2 Three treatment groups and a negative control group are analyzed. 3 The prevalence of a treatment-related neoplasm increases proportionall y to the dosage administered. 4 There are no sex differences in neoplastic responses.…”

“…Alternatives to the conventional mouse bioassay have been reviewed (3,6,14,20,22). The Tg rasH2 mouse, of cially designated CB6F1-TgN (RasH2) and also reported as the rasH2 mouse and TgHras2 mouse, is one of the alternative models speci cally mentioned in the ICH Guidelines (1).…”