Liarozole showed antitumoral activity in the Dunning AT-6sq, an
androgen-independent rat prostate
carcinoma. To investigate its potential mechanism 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 acid levels and on the differentiation status of the
tumor cells were evaluated. To follow modulation of differentiation, cytokeratins were localized in the (un)treated
tumors by immunocytochemistry and quantitatively determined by immunoblotting. Results showed that
liarozole statistically significantly reduced
tumor weight from 30 mg/kg upwards and induced accumulation of
all-trans-retinoic acid both in plasma and
tumors. In the
tumors, a statistically significant accumulation was already noted from 7.5 mg
liarozole/kg upwards. Concomitantly, the differentiation status shifted from a keratinizing towards a non-keratinizing
squamous carcinoma, which was further confirmed by the
cytokeratin profile of the
carcinoma (presence of CK 8, 10, 13, 14, 18, 19). Immunoblotting revealed an overall decrease in
cytokeratin content, except for CK 8. These findings suggest that the antitumoral properties of
liarozole might be related to an increase in the degree of
tumor differentiation through accumulation of
all-trans-retinoic acid.