INHIBITION OF GROWTH AND INDUCTION OF TGF-BETA(1) IN HUMAN HEPATOCELLULAR-CARCINOMA WITH ANDROGEN RECEPTOR BY CYPROTERONE-ACETATE IN MALE NUDE-MICE

Background/Aims: Hepatocellular carcinoma possesses androgen receptor but its true role is not known. This study aimed to investigate the ef fect of an anti-androgen cyproterone acetate on the growth of androgen receptor-positive hepatocellular carcinoma. Methods: Androgen recepto r-positive human hepatocellular carcinoma cells (KYN-1/SM-10) were sub cutaneously transplanted into male nude mice. When the tumor size was about 10 mm, animals were subcutaneously administered cyproterone acet ate (0.1 mg/day and 0.8 mg/day) or solvent alone for 21 days. Animals were serially sacrificed for measurements of testicular weight, tumor size, and cytosolic and nuclear androgen receptor levels in tumor. Pro liferating cell nuclear antigen, transforming growth factor-alpha, and transforming growth factor-beta(1) in tumor were investigated immunoh istochemically, using monoclonal antibodies. Apoptotic activity was al so studied by the lit situ DNA nick end labeling method. Results: Cypr oterone acetate depressed testicular weight, suppressed tumor growth, and decreased both cytosolic-androgen receptor and nuclear-androgen re ceptor levels dose-dependently. Numbers of proliferating cell nuclear antigen-positive cells were decreased transiently with the low dose bu t continuously with the high dose of cyproterone acetate. Transforming growth factor-alpha expression was not influenced by cyproterone acet ate, but the high dose of cyproterone acetate induced higher expressio n of transforming growth factor-beta(1), associated with increased num bers of apoptotic tumor cells, peaking on day 3. Conclusions: The inhi bition of growth of androgen receptor-positive hepatocellular carcinom a with cyproterone acetate in male nude mice could be due to G(1)-phas e cell cycle arrest, and to some extent apoptosis induced by increased synthesis of transforming growth factor-beta(1) in tumor, caused by t he direct action of cyproterone acetate through androgen receptors, as well as decreased testosterone levels in blood due to cyproterone ace tate-induced testicular atrophy.