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Chemically Induced Forestomach Papillomas in Transgenic Mice Carry Mutant Human c-Ha-ras Transgenes¹

Department of DNA Biology, School of Medicine, Tokai University, Bohseidai Isehara Kanagawa 259-II [K. A., A. S., M. Ki., M. Ka.]; Department of Pathology, Cancer Institute, Tokyo [O. H.]; and Central Institute for Experimental Animals, Kawasaki [R-i. T., M. Ka.], Japan

Forestomach papillomas and skin papillomas were induced very efficiently by a single dose administration of the chemical carcinogen methylnitrosourea (MNU) in transgenic mice (rasH2 line) carrying human hybrid c-Ha-ras genes, which encode the prototype p21 gene product. The incidence of forestomach papillomas was dose dependent; when 50 mg/kg of MNU were administered i.p., all of the transgenic mice (56 of 56) developed forestomach papillomas within 12 weeks after administration, whereas 5 and 0.5 mg/kg of MNU induced papillomas in 2 of 19 and 1 of 19 mice, respectively. Nine of 56 transgenic mice (16%) also developed skin papillomas at sites wounded by bites or scratches. Only 1 of 77 nontransgenic littermates developed forestomach papillomas after administration of 50 mg/kg of MNU, and no skin papillomas appeared within 12 weeks after MNU administration. The transgenes (integrated copy number, 5–6) in the tumors developed in 55 of 56 affected transgenic mice (98%) contained at least 1 copy of the transgene that was activated by somatic point mutation at the 12th codon, from GGC (Gly) to GAC (Asp). Because somatic point mutations at the 12th or 61st codon of transgenes have never been detected in normal tissues of transgenic mice thus far examined, these mutational activations of transgenes are tumor-specific events. RNA expression of these activated transgenes was also detected. From these results, it is suggested that somatic mutational activation of the human c-Ha-ras transgene plays a causative role in the occurrence of forestomach and skin papillomas induced by MNU administration in these transgenic mice. This transgenic mouse provides a unique screening system for chemicals that induce or suppress papillomagenesis.

¹ This research was supported in part by a Grant-in-Aid for Cancer Research and a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science and Culture, Japan; by a Grant-in-Aid from the Ministry of Health and Welfare for the Comprehensive 10 year Strategy for Cancer Control, Japan; a grant from Science and Technology Agency, Japan (to M. Ka.); and a grant from the Waksman Foundation of Japan Inc. (to M. Ki.).

² To whom requests for reprints should be addressed. Present address: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University 69, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.

Received 7/18/91. Accepted 12/ 3/91.

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