Significant experimental decrease of the hepatocellular carcinoma incidence in C3H/Sy mice after long-term administration of EB1089, a vitamin D analogue.

Abstract

EB1089, a vitamin D analogue without the acute side effects of 1alpha,25(OH)2D3, the physiologically active form of vitamin D, exerts strong antiproliferative activities in malignant cells, including hepatoma cells in vitro, and in experimental hepatomas in animals as well. It also induces cell cycle arrest and apoptosis in premalignant conditions, suggesting its application in chemopreventive trials. We examined the possible chemopreventive effect of EB1089 on hepatocellular carcinoma (HCC) incidence in C3H/Sy virgin female mice, a strain developing an incidence of 58% spontaneous HCCs. A total of 95 mice, 16 weeks old, were used. EB1089 injections of 0.5 microg/kg of body weight were given IP every other day for 2, 4, and 6 months to 51 mice (18, 19, and 14 mice, respectively). The remaining 44 mice were divided into three control groups, accordingly, and injected with the vehicle solution only. The mice were sacrificed when they appeared moribund because of their disease. The rest were sacrificed at the age of at least 80 weeks. A full autopsy was performed and liver tissue was processed for histological examination. The results obtained show that 3.9% of treated mice developed HCC, exclusively in the 2-month group, compared with 36.4% of HCCs in the control group. Our results suggest that the chemopreventive administration of EB1089 causes a very statistically significant (P < 0.0001) inhibitory effect on HCC incidence of C3H/Sy mice. This effect could be useful in a potential application on the chemopreventive control of HCCs.