Tamoxifen alone or in combination with estradiol-17β inhibits the growth and malignant transformation of hepatic hyperplastic nodules

Abstract

Hepatic hyperplastic nodules (HHNs) induced by the ‘resistant hepatocyte method’ of Solt and Farber were studied as an experimental prototype of oral contraceptive-related tumors. Cytoplasmic estrogen receptors were present in all HHNs harvested and their concentration was always less than that in normal liver. No specific cytoplasmic progestin receptors could be measured in the above tumor or liver specimens. The long-term administration of estradiol-17β (4.8–24.0 μg/day) resulted in the death of all but one of 20 animals prior to termination at 10 months. Tamoxifen (0.25–2.5 mg biweekly) which did not lead to excess mortality, decreased HHN grade (proportion of liver slice occupied by HHN) and inhihited malignant transformation. Combination therapy with single-dose estradiol-17β (4.8 μg/day) and various doses of tamoxifen (0.25–2.5 mg biweekly) in most cases reduced mortality, HHN grade and malignant transformation. Cytoplasmic progestin receptors were absent and estrogen receptors were either undetectable or present in low concentration in hepatic tumors harvested at the time of termination. Our results indicate that HHNs are hormone-dependent and that malignant transformation can be inhibited by tamoxifen alone or in combination with estradiol-17β.