Switch from antagonist to agonist of the androgen receptor blocker bicalutamide is associated with prostate tumour progression in a new model system

Advanced prostate cancer is treated by androgen ablation and/or androgen re ceptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androge n ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-de pleted medium for 87 passages. The new LNCaP cell subline established in th is manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative res ponse to androgen until passage 75. Maximal proliferation of LNCaP-abl cell s was achieved at 0.001 nM of the synthetic androgen methyltrienolone (R188 1), whereas 0.01 nM of this compound induced the same effect in parental ce lls. At later passages (> 75), androgen exerted an inhibitory effect on gro wth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimul ated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl c ells increased approximately fourfold. The basal AR transcriptional activit y was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated rep orter gene activity in LNCaP-abl cells even at 0.01 nM, whereas 0.1 nM of R 1881 was needed for induction of the same level of reporter gene activity i n LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCa P cells showed agonistic effects on AR transactivation activity in LNCaP-ab l cells and was not able to block the effects of androgen in these cells. T he non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of r eporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the fir st time that the non-steroidal anti-androgen bicalutamide acquires agonisti c properties during long-term androgen ablation, These findings may have re percussions on the natural course of prostate cancer with androgen deprivat ion and on strategies of therapeutic intervention. (C) 1999 Cancer Research Campaign.