Preclinical activity of ketoconazole in combination with calcitriol or the vitamin D analogue EB 1089 in prostate cancer cells

Purpose: Ketoconazole is a general inhibitor of P450 enzymes, of which some are necessary for androgen biosynthesis and the metabolism of vitamin D compounds. We tested the growth inhibitory activity of ketoconazole combined with 1,25-dihydroxyvitamin D3 (calcitriol) and with the vitamin D analogue EB 1089 in a preclinical model of prostate cancer. Materials and Methods: Clonal assays with primary cultures of human prostatic cancer cells were performed to test anti-proliferative effects of ketoconazole alone or in combination with calcitriol or EB 1089. Enzyme substrate reactions were done to determine whether the ability of ketoconazole to potentiate the activity of calcitriol or EB 1089 was due to the inhibition of 25-hydroxyvitamin D3-24-hydroxylase (24-hydroxylase), the enzyme that initiates conversion of active vitamin D compounds to inactive products. Results: Ketoconazole, calcitriol and EB 1089 each inhibited the growth of prostatic cancer cells. In combination 0.1 mug./ml. ketoconazole potentiated growth inhibitory activity of calcitriol 50-fold and EB 1089 10-fold. Induction of 24-hydroxylase by calcitriol or EB 1089 was partially blocked by this level of ketoconazole. Conclusions: Combination therapy-with-ketoconazole and calcitriol. or. EB 1089 may enhance antitumor activities of vitamin D compounds for prostate cancer and alleviate side effects of vitamin D deficiency that are likely associated with ketoconazole therapy.