Journal Article

Chemically induced lung and forestomach neoplasias in transgenic mice carry mutant forms of the human c-Ha-<i>ras</i> transgene

Kumiko Ogawa, Katsumi Imaida, Tsuneo Masui, Mayumi Kawabe, Ryohei Hasegawa, Koji Kato, Nobuyuki Ito and Tomoyuki Shirai

in Carcinogenesis

Volume 17, issue 2, pages 341-345
Published in print February 1996 | ISSN: 0143-3334
Published online February 1996 | e-ISSN: 1460-2180 | DOI:
Chemically induced lung and forestomach neoplasias in transgenic mice carry mutant forms of the human c-Ha-ras transgene

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Susceptibility to lung carcinogens and genetic changes in neoplastic lesions were investigated in transgenic mice carrying a human hybrid c-Ha-ras gene, encoding a prototype p21 gene product. Nine-week-old male and female transgenic mice and non-transgenic littermates were injected i.p. with 6-nitrochrysene (6NC) three times biweekly or administerted urethane in their drinking water for 3 weeks. Control mice were given dimethylsulfoxide(DMSO), the solvent for 6NC,alone. The incidences of lung adenocarcinomas were four out of seven female (57%)transgenic mice treated with 6NC and three out of three males (100%) and three out of three females (100%) receiving urethane. No adenocarcinomas were observed in control animals or non-transgenic mice. Adenomas developed in all treated groups, but the incidence and multiplicity were higher in transgenic animals than in their non-transgenic counterparts. In the 6NC-treated group, forestomach papillomas and squamous cell carcinomas were also observed in both male (25 and 50%) and female (56 and 33%) transgenic mice. PCR-SSCP and DNA sequence analysis of these induced lesions revealed point mutations at codon 61 of transgenic human c-Ha-ras, from CAG (Gin) to CTG (Leu) or CAG (Gin) to AAG (Lyn) in lung hyperplasias (two out of three), an adenoma (one out of two), adenocarcinomas (five out of seven) and forestomach squamous cell carcinomas (four out of five). Mutations were not observed in forestomach papillomas. No changes in mouse Ha-ras or KI-ras were found in any lesions. Furthermore, p21 overexpression was not evident in lung or forestomach tumors on immunohistochemical analysis. These findings indicate a high sensitivity to lung carcinogens in transgenicmice carrying the human c-Ha-ras gene and that this might be effected by mutational activation.

Journal Article.  0 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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