Introduction: The androgen resistance of some prostate cancer patients may be due to transcriptional inactivation of the androgen receptor (AR) gene catalyzed by cytosine DNA methyltransferase.
Materials and methods: To determine if an inhibitor of cytosine DNA methyltransferase, 5,6-dihydro-5'-azacytidine (DHAC), can restore the androgen sensitivity in androgen-insensitive human prostate carcinoma cell lines in vitro, we cultured androgen-insensitive (PC3, DU-145, and TSUPrl) and androgen-responsive (LNCaP) cells with subcytotoxic concentrations (< or = IC50) of DHAC for 14 days followed by exposure to dihydrotestosterone (DHT) or to hydroxyflutamide for 7 days.
Results and conclusions: Only DHAC-treated DU-145 cells showed growth stimulation by 10(-11) to 10(-9) M DHT and a partial inhibition by 10(-5) and 10(-6) M hydroxyflutamide. However, since DU-145 is the only cell line tested that is known to have a hypermethylated AR promoter, the observed effects may be due to a partial demethylation of the AR by DHAC. Our data provide an evidence that cytosine DNA methyltransferase inhibitors can restore androgen responsiveness in androgen-refractory tumor cells, which are then sensitive to growth inhibition by antiandrogens.