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Interlaboratory Comparison of Short-Term Carcinogenicity Studies Using CB6F1-rasH2 Transgenic Mice

Planning and Promotion Department, New Drug Development Division, Sankyo Co, Ltd, Tokyo, Japan

Shinya Sehata

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, 717 Fukuroi, Shizuoka 437-0065, Japan, sehata{at}fuku.sankyo.co.jp

Takanori Maejima

Medicinal Safety Research Laboratories, Sankyo Co, Ltd, 717 Fukuroi, Shizuoka 437-0065, Japan

Toshio Imai

Eisai Co, Ltd, Gifu, Japan

Mikinori Tor

Shionogi & Co, Ltd, Osaka, Japan

Hiroshi Satoh

Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan

Kaoru Toyosawa

Dainippon Pharmaceutical Co, Ltd, Osaka, Japan

Zen-Yo Tanakamaru

Takeda Chemical Industries, Ltd, Osaka, Japan

Tamiko Adachi

Tanabe Seiyaku Co, Ltd, Osaka, Japan

Shigeru Hisada

Teikoku Hormone Mfg Co, Ltd, Kawasaki, Japan

Makoto Ueda

Nippon Shinyaku Co, Ltd, Kyoto, Japan

Hiroyuki Ogasawara

Wyeth Lederle Japan, Ltd, Saitama, Japan

Masahiro Matsumoto

Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan

Kiyoshi Kobayashi

Mitsubishi Pharma Corporation, Yokohama, Japan

Mamoru Mutai

Mitsubishi Pharma Corporation, Yokohama, Japan

Toshimi Usui

Central Institute for Experimental Animals, Kawasaki, Japan

In order to evaluate a short-term carcinogenicity testing system using CB6F1-Tg rasH2 ( rasH2-Tg) mice carrying a human prototype c-Ha-ras gene, 26-week studies were conducted in 12 different facilities as a part of an International Life Science Institute Health and Environmental Science Institute (ILSI HESI) international collaborative project. In each study N-methyl-N-nitrosourea (MNU) was administered to a separate group of rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. We herein have summarized the mortality, body weight change, and neoplastic and nonneoplastic lesions detected in these positive control groups as representative historical positive control data. Also, we performed an interlaboratory comparison of the response of rasH2-Tg mice to MNU based on the data of 11 positive control groups from these studies. Although the body weight of rasH2-Tg mice showed lower values than that of non-Tg mice during the experimental period, body weight gain in the rasH2-Tg mice was similar to that in non-Tg mice. The mortality of rasH2-Tg mice during the study period was very low, the same as for the non-Tg mice. Incidences of spontaneous alveolar/bronchiolar adenomas and splenic hemangiomas/hemangiosarcomas were also low in the rasH2-Tg mice. Nonneoplastic lesions detected in the rasH2-Tg mice were similar to those in non-Tg mice, excluding the incidence of myopathy. There were interlaboratory differences in mortality and incidence of some lesions in the MNU-treated groups. However, the causes of death were common among the 11 laboratories and almost all the MNU-treated rasH2-Tg mice developed forestomach squamous cell papillomas/carcinomas or malignant lymphomas. This suggests that there is no appreciable difference in the response of the rasH2-Tg mouse to MNU used as a positive control. Therefore, it is concluded that MNU would be an adequate positive control compound in this testing system.

Key Words: rasH2-Tg mouse • human prototype c-Ha-ras gene • short-term carcinogenicity testing • ILSI HESI international collaborative project • N-methyl-N-nitrosourea.

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Toxicologic Pathology, Vol. 31, No. 2, 191-199 (2003)
DOI: 10.1080/01926230390183670


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