CHEMICALLY-INDUCED LUNG AND FORESTOMACH NEOPLASIAS IN TRANSGENIC MICECARRY MUTANT FORMS OF THE HUMAN C-HA-RAS TRANSGENE

0Susceptibility 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 mal e and female transgenic mice and non-transgenic littermates were injec ted i.p. with 6-nitrochrysene (6NC) three times biweekly or administer ed urethane in their drinking water for 3 weeks. Control mice were giv en dimethylsulfoxide (DMSO), the solvent for 6NC, alone. The incidence s of lung adenocarcinomas were four out of seven female (57%) transgen ic mice treated with 6NC and three out of three males (100%) and three out of three females (100%) receiving urethane. No adenocarcinomas we re observed in control animals or non-transgenic mice. Adenomas develo ped in all treated groups, but the incidence and multiplicity were hig her in transgenic animals than in their non-transgenic counterparts. I n the 6NC-treated group, forestomach papillomas and squamous cell carc inomas were also observed in both male (25 and 50%) and female (56 and 33%) transgenic mice. PCR-SSCP and DNA sequence analysis of these ind uced lesions revealed point mutations at codon 61 of transgenic human c-Ha-ras, from CAG (Gln) to CTG (Leu) or CAG (Gln) to AAG (Lyn) in lun g hyperplasias (two out of three), an adenoma (one out of two), adenoc arcinomas (five out of seven) and forestomach squamous cell carcinomas (four out of five). Mutations were not observed in forestomach papill omas. 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 immunohistohemical analysis. These findings indicate a high sensitivity to lung carcinogens in transgenic mice carrying the human c-Ha-ras gene and that this might be effected by mutational activatio n.