Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing.

Abstract

Carcinogenicity testing is indispensable for identifying environmental carcinogens and for evaluating the safety of drugs in the process of development. Conventional 2-year rodent bioassays are one of the most resource-consuming tests in terms of animals, time, and costs. Development of rapid carcinogenicity testing systems that can assess carcinogenicity within a short period has become a social demand and is essential to improve efficacy in the identification of environmental carcinogens as well as in the development of new drugs. In this review we introduce the rapid carcinogenicity testing system using transgenic (Tg) mice carrying the human prototype c-Ha-ras gene, namely rasH2 mouse (CB6F1-TgHras2 mouse is the same mouse). The studies have been conducted to validate the rasH2 mouse as a model for the rapid carcinogenicity testing system. Our current validation studies revealed that rasH2 mice are able to detect various types of mutagenic carcinogens within 6 months. The rasH2 mice may also be able to detect various nonmutagenic carcinogens. The validation studies also revealed that rasH2 mice are generally much more susceptible to both mutagenic and nonmutagenic carcinogens than control non-Tg mice. No significant tumor induction has been observed in rasH2 mice with either mutagenic or nonmutagenic noncarcinogens. More rapid onset and higher incidence of more malignant tumors can be expected with a high probability after treatment with various carcinogens in the rasH2 mice than in control non-Tg mice. The rasH2 mouse appears to be a promising candidate as an animal model for development of a rapid carcinogenicity testing system.

The use of genetically modified mice in cancer risk assessment: Challenges and limitations

“…GM animals have been developed and are being used to complement or, in some cases, replace the chronic rodent bioassays that have traditionally been performed for assessing cancer risks (reviewed in Boverhof et al, 2011; French et al, 2001b; Pritchard et al, 2003; Storer et al, 2010; Tennant et al, 1995; Yamamoto et al, 1998a). A large number of GM animals have been used and/or are currently being developed to investigate the role of specific genes and signaling pathways in chemical carcinogenesis (Boverhof et al, 2011; Goldsworthy et al, 1994; Macleod & Jacks, 1999).…”

“…Summaries of the results from the three models ( Trp53 +/− , Tg.AC and ras H2) that have had substantial evaluation to date have been presented in several reviews (Jacobs, 2005; Pritchard et al, 2003; Spalding et al, 2000; Storer et al, 2010; Tennant et al, 1999a; Yamamoto et al, 1998a). In these reports, a variety of carcinogenic and noncarcinogenic chemicals have been tested with frequently encouraging results.…”

“…In these reports, a variety of carcinogenic and noncarcinogenic chemicals have been tested with frequently encouraging results. The Trp53 +/− model is reported to detect primarily genotoxic carcinogens whereas the Tg.AC and the ras H2 models exhibit a broader range of sensitivity detecting both mutagenic and nonmutagenic carcinogens (Tennant et al, 1999a; Yamamoto et al, 1998a). However, the results are often presented in summary form in categorical (positive or negative) and not quantitative terms.…”

“…NTP has also tested other models such as the chimeric B6.19-P16 INK4A/ p19 ARF using benzene (NTP, 2007a), glycidol (NTP, 2007b) and phenolphthalein (NTP, 2007c). The ras H2 model was evaluated primarily by a group of Japanese organizations comprising the Central Institute for Experimental Animals (CIEA), the National Institute for Health Sciences and several pharmaceutical companies (Yamamoto et al, 1998a), and has been reviewed for its utility for preclinical testing (Storer et al, 2010). The Xpa −/− and/or Xpa / Trp53 +/− knockout mouse models were tested by the National Institute of Public Health and the Environment in the Netherlands (van Kreijl et al, 2001; van Kreijl & van Steeg, 1998).…”

“…Over the past two decades, there has been considerable interest in the development and application of short-term or accelerated cancer bioassays using GM animals that exhibit high sensitivity to chemically induced cancers (Boverhof et al, 2011; Gulezian et al, 2000; Mahler et al, 1998; Pritchard et al, 2003; Tennant et al, 1999a; Yamamoto et al, 1998a). The basis for this approach is that rodents with an alteration in a conserved gene critical for tumorigenesis could be developed as test organisms for accelerated cancer bioassays.…”