LIAROZOLE, AN ANTITUMOR DRUG, MODULATES CYTOKERATIN EXPRESSION IN THEDUNNING AT-6SQ PROSTATIC-CARCINOMA THROUGH IN-SITU ACCUMULATION OF ALL-TRANS-RETINOIC ACID

Liarozole showed antitumoral activity in the Dunning AT-6sq, an androg en-independent rat prostate carcinoma. To investigate its potential me chanism of action, the effects of the drug doses (ranging from 3.75 to 80 mg/kg b.i.d.) on endogenous plasma and tissue all-trans-retinoic a cid levels and on the differentiation status of the tumor cells were e valuated. To follow modulation of differentiation, cytokeratins were l ocalized in the (un)treated tumors by immunocytochemistry and quantita tively determined by immunoblotting. Results showed that liarozole sta tistically significantly reduced tumor weight from 30 mg/kg upwards an d induced accumulation of all-trans-retinoic acid both in plasma and t umors. In the tumors, a statistically significant accumulation was alr eady noted from 7.5 mg liarozole/kg upwards. Concomitantly, the differ entiation status shifted from a keratinizing towards a non-keratinizin g squamous carcinoma, which was further confirmed by the cytokeratin p rofile of the carcinoma (presence of CK 8, 10, 13, 14, 18, 19). Immuno blotting revealed an overall decrease in cytokeratin content, except f or CK 8. These findings suggest that the antitumoral properties of lia rozole might be related to an increase in the degree of tumor differen tiation through accumulation of all-trans-retinoic acid. (C) 1995 Wile y-Liss, Inc.