Rare activation of the human c-Ha-ras transgene of mice in hemangioendothelial sarcomas and liver tumors induced by Glu-P-1.

Abstract

A transgenic mouse (Tg), having the human c-Ha-ras proto-oncogene, has been demonstrated to develop hemangioendothelial sarcomas (HESs) which are associated with the transgene mutation, but not to develop liver tumors. In this study, we examined the effects of 2-amino-6-methyldipyrido [1,2-a:3',2'-d] imidazole (Glu-P-1), a food-borne carcinogen, which has been demonstrated to induce HESs and liver tumors in CDF1 mice, on Tg mice. Chronic administration of 0.05% Glu-P-1 in the diet induced HESs in Tg (7/17), but not in 18 non-transgenic mice (N-Tg). With basal diet, two out of 17 Tg but none of 22 N-Tg, developed HESs. In contrast, Glu-P-1 administration induced liver tumors, both in Tg and in N-Tg; 16/17 in Tg and 13/18 in N-Tg. The incidence of hepatocellular carcinomas in Tg was higher than that in N-Tg (8/17 versus 3/18). With basal diet, only one out of 17 Tg and none of 22 N-Tg developed liver tumors. The Ha-ras mutation in tumors developed by the groups administered Glu-P-1, was examined. No mutations were detected in the transgene and mouse c-Ha-ras genes in all three HESs examined. In contrast, when 29 liver tumors taken from Tg were examined, two mutations of the transgene were detected in two HCCs. No mouse c-Ha-ras gene mutations were detected in any of the 47 liver tumors examined, which had developed in Tg and N-Tg mice. These results suggest that the transgene plays a role in the development of HESs induced by Glu-P-1, but not as a result of its mutation. Further, the transgene plays no significant role in the development of liver tumors induced by Glu-P-1, but does play a role in the malignant conversion of some liver tumors, as a result of its mutation.

• Authors: R Inoue, T Ushijima, M Katami, H Kushida, K Wakabayashi, H Sato, M Asamoto, M Katsuki, T Sugimura, M Nagao
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 87 Issue 6 Pg. 583-8 (Jun 1996) ISSN: 0910-5050 [Print] Japan
• PMID: 8766521 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Neoplasm
• Imidazoles
• MAS1 protein, human
• Mutagens
• Proto-Oncogene Mas
• 2-amino-6-methyldipyrido(1,2-a-3',2'-d)imidazole

Topics

• Animals
• Base Sequence
• DNA, Neoplasm (chemistry)
• Female
• Genes, ras (drug effects, genetics)
• Hemangiosarcoma (genetics)
• Humans
• Imidazoles (pharmacology)
• Liver Neoplasms (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Molecular Sequence Data
• Mutagens (pharmacology)
• Mutation
• Polymerase Chain Reaction
• Polymorphism, Single-Stranded Conformational
• Proto-Oncogene Mas