抄録
Female Syrian golden hamsters were given a subcutaneous injection of 0.6 mg of N-methyl-N-nitrosourethane (MNUR) every 2 weeks for 8 weeks (a total of 5 doses) and then maintained without any treatment for the next 26 weeks. The MNUR-induced bronchiolo-alveolar cell tumors were all adenomas composed of basophilic or clear cells in a papillary growth pattern or papillary/solid tumors consisting of pleomorphic cells. Ultrastructurally, most of the tumor cells had the lamellar bodies characteristic of alveolar type II cells in their cytoplasm. Positive cyclin D1 immunostaining was associated with pleomorphic cell type adenomas, whereas no overexpression of p53 protein, hsp70 or mdm2 gene protein was detected in any of the tumors. The lung tumor samples were examined for the presence of mutations in the K-ras gene in codon 12, 13, and 61 by a non-isotopic method for selective oligonucleotide hybridization after PCR amplification of DNA from formalin fixed tissue embedded in paraffin. Lung tumors from 6 of 18 (33%) tumor bearers contained a point mutation in codon 13 or 61, 3 involving GGC→GAC transitions at the second base of codon 13 and 3 affecting the 61st codon, one CAA→CTA, and two CAA→CGA. No mutations were detected in codon 12.
These findings indicate that, at least, a point mutation of the K-ras gene was related to the development of bronchiolo-alveolar cell adenomas induced by MNUR and may suggest that cyclin DI overexpression in pleomorphic cell type tumors plays a role in the process of malignant transformation.
