Prostate cancer has become the most commonly diagnosed cancer in US men. 1 Today most prostate cancers from patients treated with androgen ablation progress from an androgendependent to an androgen-independent state. With the cloning of the androgen receptor cDNA2 and the discovery that some mutant androgen receptors may be able to change steroid and antiandrogen specificity, 3 the hypothesis that mutations in androgen receptors may be the reason why hydroxyflutamide, the active metabolite of flutamide, can activate androgen receptor target genes and stimulate (rather than inhibit) prostate cancer growth, is becoming widely accepted. The same mechanism has been used to explain the flutamide withdrawal syndrome, in which patients who experience an increase in prostate-specific antigen (PSA) while taking flutamide, have a decrease in PSA after withdrawal of treatment. Since this syndrome often heralds the failure of androgen-ablative therapy, elucidating the mechanism by which hydroxyflutamide increases the expression of PSA may provide a new approach to delaying or reversing the emergence of androgen independence.

The discovery of ARA70, the first co-activator for androgen receptor, and the observation that higher concentrations of hydroxyflutamide may have weak agonistic activity in the presence of ARA70, 4 has allowed us to investigate this phenomenon further. We present evidence that hydroxyflutamide can activate androgen receptor target genes, such as PSA and MMTV-LTR, in the presence of ARA70. While AR877 mutation may increase potency of hydroxyflutamide (figure, B, 7; C, 7), a mutated androgen receptor alone has only a small capacity to mediate hydroxyflutamide induction of PSA in DU145 cells (figure, C, 1–4). Our data suggest that in the absence of androgens, a condition similar to some of the later stages of prostate cancer under maximal androgen ablative therapy, hydroxyflutamide