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Toxicologic Pathology
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Mutation and Overexpression of the Transgene in Ethylnitrosourea-Induced Tumors in Mice Carrying a Human Prototype c-Ha-ras Gene

Kaoru Toyosawa

Safety Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Osaka 564-0053, Japan, kaoru-toyozawa{at}dainippon-pharm.co.jp

Kohji Tanaka

Safety Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Osaka 564-0053, Japan

Toshio Imai

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Kazuo Yasuhara

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Takatoshi Koujitani

Safety Research Laboratories, Dainippon Pharmaceutical Co, Ltd, Osaka 564-0053, Japan, Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Masao Hirose

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan

Kunitoshi Mitsumori

Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan, Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan

To investigate mechanisms underlying accelerated carcinogenesis in mice carrying a human prototype c-Ha- ras gene (rasH2 mouse), mutations and the expression profile of the transgene were evaluated in 14 tumors induced by a single injection of ethylnitrosourea (ENU), with or without additional beta-estradiol 3-benzoate (EB) treatment. Although no codon 12 mutations were detected, changes in codon 61 were evident in all lung adenocarcinomas, skin squamous cell carcinomas and forestomach squamous cell carcinomas examined. The mRNA levels of the transgene in these lesions were also elevated 1.71- to 4.77-fold, 3.04- to 5.18-fold, and 3.00- to 5.67-fold, respectively, in comparison with those in the normal livers of rasH2 mice. The results obtained in this study suggest that mutations in codon 61 and amplification of the transgene play key roles in the carcinogenesis induced by ENU in rasH2 mice.

Key Words: Human prototype c-Ha-ras transgenic mouse • rasH2 mouse • ethylnitrosourea (ENU) • transgene • mutation • overexpression.

Toxicologic Pathology, Vol. 31, No. 5, 491-495 (2003)
DOI: 10.1080/01926230390224683
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