Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-<i>ras</i> gene than in control non-transgenic mice

Yamamoto, Satoshi; Mitsumori, Kunitoshi; Kodama, Yukio; Matsunuma, Naochika; Manabe, Sunao; Okamiya, Hideaki; Suzuki, Hiroshi; Fukuda, Tatsuya; Sakamaki, Yoshiyuki; Sunaga, Masao; Nomura, Gakushi; Hioki, Kyoji; Wakana, Shigeharu; Nomura, Tatsuji; Hayashi, Yuzo

doi:10.1093/carcin/17.11.2455

Cited by 131 publications

(125 citation statements)

References 14 publications

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“…The positive control for Tg rasH2 mouse studies has generally been a single intraperitoneal injection of N-methyl-Nnitrosourea (MNU) at a dose of 75 mg/kg (8,19,21). Single 37.5 or 75 mg/ kg injections of MNU appear to be appropriate treatment regimens for Tg rasH2 positive control groups (8).…”

Section: Introductionmentioning

confidence: 99%

The Tg rasH2 Mouse in Cancer Hazard Identification

Morton¹,

Alden²,

Roth³

et al. 2002

Toxicol Pathol

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The Tg rasH2 transgenic mouse has been developed as an alternative to the lifetime mouse bioassay to predict the carcinogeni c potential of chemicals. Unlike the p53 / mouse, the Tg rasH2 mouse is sensitive to both genotoxic and nongenotoxi c carcinogens . The Tg rasH2 mouse, of cially designated CB6F1-TgN (RasH2), contains multiple copies of the human c-Ha-ras oncogen e and promoter within its genome. These mice develop spontaneou s and chemically induced neoplasms earlier in life and in greater numbers than wild-type mice, re ecting their enhanced sensitivity to neoplasia. The most common spontaneous neoplasms in control Tg rasH2 mice 8 to 9 months of age are lung adenomas and carcinomas (7.4% incidence), splenic hemangioma s and hemangiosarcoma s (5.4%), forestomach squamous cell papillomas and carcinomas (2.4%), and skin neoplasms (1.2%). Simulations have demonstrated that 20 to 25 mice/sex/treatment group are required to provide the assay with adequate statistical power. Four of 6 known or suspected human carcinogens tested in Tg rasH2 mice were positive in this assay. For 19 nonmutageni c agents testing positive in conventiona l rodent bioassays, 7 chemicals were positive, 10 chemicals were negative, and 2 were equivocal. None of the 10 nonmutageni c rodent carcinogen s that were negative in the Tg rasH2 mouse model are considered to be human carcinogens . All nonmutageni c chemicals that were negative in the conventiona l rodent bioassays were also negative in the Tg rasH2 model. Results for 15 of 18 mutageni c chemicals tested in Tg rasH2 mice agreed with the results of conventiona l rodent bioassays, and 3 results were equivocal. The Tg rasH2 mouse model appears to predict known or suspected human carcinogen s as well as the traditional mouse bioassay, but with fewer positive results for nongenotoxi c compounds that are not considered human carcinogens . The Tg rasH2 mouse model is the most thoroughly tested in vivo alternative to the lifetime mouse bioassay for nongenotoxi c compounds administered by oral or parenteral routes. The U.S. FDA Carcinogenicit y Assessment Committee has determined that the Tg rasH2 model has been adequately evaluated for consideration for carcinogenicity testing of pharmaceutica l candidates and its use could contribute to the weight of evidence for carcinogenicity assessment. The FDA will consider proposals to replace lifetime mouse carcinogenicity studies with 6-month Tg rasH2 mouse studies to support pharmaceutical registration on a case-by-cas e basis.

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Section: Introductionmentioning

confidence: 99%

The Tg rasH2 Mouse in Cancer Hazard Identification

Morton¹,

Alden²,

Roth³

et al. 2002

Toxicol Pathol

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“…It has been reported that incidence of spontaneous tumors is generally low in rasH2-Tg mice during a 6-month study (20). Therefore, the rasH2-Tg mice model might be a useful tool for identi cation of genotoxic and/or nongenotoxic carcinogens for humans (30,31).…”

Section: Introductionmentioning

confidence: 99%

Twenty-Six-Week Carcinogenicity Study of Chloroform in CB6F1 rasH2-Transgenic Mice

Sehata¹,

Maejima²,

Watanabe³

et al. 2002

Toxicol Pathol

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The carcinogenic potential of chloroform was evaluated in a short-term carcinogenicity testing system using CB6F 1 rasH2-Tg (rasH2-Tg) mice. Chloroform was administered to rasH2-Tg males at doses of 28, 90, or 140 mg/kg and rasH2-Tg females at 24, 90, or 240 mg/kg by oral gavage for 26 weeks. Wild-type (non-Tg) male and female mice received doses of 140 mg/kg and 240 mg/kg, respectivel y. N-methyl-N-nitrosourea was administered to rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. In both the rasH2-Tg and non-Tg mice, there was no signi cant increase in the incidence of neoplastic lesions by chloroform treatment. The incidence of hepatocellular foci in the rasH2-and non-Tg females receiving 240 mg/kg was increased. Forestomach tumors and malignant tumors occurred in most of the rasH2-mice in the positive control group. Swelling or vacuolation of hepatocytes , a toxic change induced by chloroform, occurred in both the rasH2-Tg and non-Tg mice. It is concluded that chloroform, a putative human noncarcinogen , did not show evidence of carcinogenic potential in the present study using rasH2-Tg mice. This study suggests that the rasH2-Tg mouse model may not be appropriate for detecting nongenotoxi c carcinogens. However, the sensitivity of rasH2-Tg mice to nongenotoxi c carcinogen s should be assessed with consideration of the results from the other ILSI-HESI project studies.

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“…Transgenic animals harboring an oncogene and/or animals lacking a tumor suppressor gene are expected to be more susceptible to various carcinogens than normal animals [18]. Tg-rasH2 mice hemizygously carrying the prototype human c-Ha-ras gene, which were established by Saitoh et al [23], show high and rapid susceptibility to various carcinogens and are considered to be promising as an animal model for an alternative rapid carcinogenicity test [19,26]. In addition, the phenotypes of high and rapid carcinogenesis in transgenic mice may be useful for evaluating new anticancer drugs or cancer prevention.…”

Section: Introductionmentioning

confidence: 99%

Induction of Drug Metabolism-Related Enzymes by Methylcholanthrene and Phenobarbital in Transgenic Mice Carrying Human Prototype c-Ha-ras Gene and Their Wild Type Littermates.

et al. 2001

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Transgenic mice hemizygously carrying human c-Ha-ras proto-oncogene, TgrasH2 show very sensitive and facilitated carcinogenicity to various carcinogens. In this study, activities of certain enzymes related to drug metabolism and energy metabolism were measured in microsome and cytosol fractions of livers of Tg-rasH2 mice and their wild type littermates with both sexes treated with 3-methylcholanthrene (MC) and phenobarbital (PB). Aminopyrine N-demethylase activities increased significantly in livers of all mice treated with PB. MC and PB treatments induced significant increases in activities of UDP-glucuronosyltransferase and S-adenosyl homocysteinase compared to those in the non-treated groups in microsome fractions from all mice. In cytosol fractions of livers of all mice, glutathione S-transferase activity was significantly induced in the PB treated groups. There were no significant differences in activities of lactate dehydrogenase, glucose 6-phosphate dehydrogenase, pyruvate kinase and glucose 6-phosphatase related to energy metabolism in livers and kidneys among all mice. TgrasH2 mice showed stable activities of enzymes related to drug detoxication and energy metabolism similar to those of non-transgenic mice. These results suggest that the human c-Ha-ras transgene may not affect drug metabolism-related enzymes, and the facilitated carcinogenic response in the Tg-rasH2 mouse is not due to these enzymatic disorders.

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Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgenic mice

Cited by 131 publications

References 14 publications

The Tg rasH2 Mouse in Cancer Hazard Identification

The Tg rasH2 Mouse in Cancer Hazard Identification

Twenty-Six-Week Carcinogenicity Study of Chloroform in CB6F1 rasH2-Transgenic Mice

Induction of Drug Metabolism-Related Enzymes by Methylcholanthrene and Phenobarbital in Transgenic Mice Carrying Human Prototype c-Ha-ras Gene and Their Wild Type Littermates.

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