RARE ACTIVATION OF THE HUMAN C-HA-RAS TRANSGENE OF MICE IN HEMANGIOENDOTHELIAL SARCOMAS AND LIVER-TUMORS INDUCED BY GLU-P-1

A transgenic mouse (Tg), having the human c-Ha-ras proto-oncogene, has been demonstrated to develop hemangioendothelial sarcomas (HESs) whic h are associated with the transgene mutation, but not to develop liver tumors. In this study, we examined the effects of 2-amino-6-methyldip yrido [1,2-a:3',2'-d] imidazole (Glu-P-1), a food-borne carcinogen, wh ich has been demonstrated to induce HESs and liver tumors in CDS mice, on Tg mice. Chronic administration of 0.05% Glu-P-1 in the diet induc ed HESs in Tg (7/17), but not in 18 non-transgenic mice (N-Tg). With b asal diet, two out of 17 Tg but none of 22 N-Tg, developed HESs. In co ntrast, 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 adminis tered Glu-P-1, was examined. No mutations were detected in the transge ne and mouse c-Ha-ras genes in all three HESs examined. In contrast, w hen 29 liver tumors taken from Tg were examined, two mutations of the transgene were detected in two HCCs. No mouse c-sa-ras gene mutations were detected in any of the 47 liver tumors examined, which had develo ped in Tg and N-Tg mice. These results suggest that the transgene play s a role in the development of HESs induced by Glu-P-1, but not as a r esult of its mutation. Futher, 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 o f its mutation.